Imidazopyridazine and imidazothiadiazole compounds

ABSTRACT

The present invention provides imidazopyridazine compounds or imidazothiadiazole compounds of Formula I having the structure: (I) wherein X 1 , X 2 , X 3 , X 4 , X 5 , Y, W, R 1 , R 2 , R 3 , R 4 , R 5  and (II) are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments for treating or preventing thromboembolic disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. provisional patentApplication No. 62/120,971, filed on Feb. 26, 2015, the contents ofwhich are incorporated herein in their entirety by reference.

FIELD OF THE INVENTION

The present invention provides novel imidazopyridazine andimidazothiadiazole inhibitors of platelet aggregation which are usefulin preventing or treating thromboembolic disorders. This invention alsorelates to pharmaceutical compositions containing these compounds andmethods of using the same.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), syntheticpentasaccharides, and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®).

Current anti-platelet therapies have limitations including increasedrisk of bleeding as well as partial efficacy (relative cardiovascularrisk reduction in the 20 to 30% range). Thus, discovering and developingsafe and efficacious oral or parenteral antithrombotics for theprevention and treatment of a wide range of thromboembolic disordersremains an important goal.

Alpha-thrombin is the most potent known activator of plateletaggregation and degranulation. Activation of platelets is causallyinvolved in atherothrombotic vascular occlusions. Thrombin activatesplatelets by cleaving G-protein coupled receptors termed proteaseactivated receptors (PARs). PARs provide their own cryptic ligandpresent in the N-terminal extracellular domain that is unmasked byproteolytic cleavage, with subsequent intramolecular binding to thereceptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic thesequence of the newly formed N-terminus upon proteolytic activation caninduce signaling independent of receptor cleavage. Platelets are a keyplayer in atherothrombotic events. Human platelets express at least twothrombin receptors, commonly referred to as PAR1 and PAR4. Inhibitors ofPAR1 have been investigated extensively, and several compounds,including vorapaxar and atopaxar have advanced into late stage clinicaltrials. Recently, in the TRACER phase III trial in ACS patients,vorapaxar did not significantly reduce cardiovascular events, butsignificantly increased the risk of major bleeding (Tricoci, P. et al.,N. Eng. J. Med., 366(1):20-33 (2012). Vorapaxar is currently beingmarketed as Zontivity® by Merck. Thus, there remains a need to discovernew antiplatelet agents with increased efficacy and reduced bleedingside effects.

There are several early reports of preclinical studies of PAR4inhibitors. Lee, F-Y. et al., “Synthesis of1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole Analogues as NovelAntiplatelet Agents”, J. Med. Chem., 44(22):3746-3749 (2001) disclosesin the abstract that the compound

“was found to be a selective and potent inhibitor of protease-activatedreceptor type 4 (PAR4)-dependent platelet activation.”

Compound 58 is also referred to as YD-3 in Wu, C-C. et al., “SelectiveInhibition of Protease-activated Receptor 4-Dependent PlateletActivation by YD-3”, Thromb. Haemost., 87:1026-1033 (2002). Also, seeChen, H. S. et al., “Synthesis and antiplatelet activity of ethyl4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives”, Bioorg. Med.Chem., 16:1262-1278 (2008).

EP1166785 A1 and EP0667345 disclose various pyrazole derivatives whichare useful as inhibitors of platelet aggregation.

The PCT publications WO2013/163279, WO2013/163244 and WO2013/163241disclose various PAR4 antagonists which are useful as inhibitors ofplatelet aggregation.

SUMMARY OF THE INVENTION

It has been found that compounds of Formula (I) in accordance with thepresent invention are PAR4 antagonists which inhibit plateletaggregation in gamma-thrombin induced platelet aggregation assays.

wherein the various moieties are as defined herein.

Accordingly, the present invention provides novel imidazopyridazine andimidazothiadiazole analogues which are PAR4 antagonists and are usefulas selective inhibitors of platelet aggregation, includingstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrug esters thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugesters thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrug esters thereof.

The present invention also provides a method for the treatment orprophylaxis of thromboembolic disorders comprising administering to apatient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrug esters thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrug esters thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrug esters thereof, for themanufacture of a medicament for the treatment or prophylaxis of athromboembolic disorder.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION

In one embodiment, the present invention provides imidazopyridazine orimidazothiadiazole compounds, stereoisomers, tautomers, salts, solvatesor prodrugs thereof, of Formula:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

the dashed line represents an optional double-bond with the proviso thatonly one of the two dashed line double bonds exists at the same time;

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S; or

X¹ is N and X² is NR⁸; or

X¹ is NR⁸ and X² is N; or

X¹ is NR⁸ and X² is CR^(1a); or

X¹ is CR^(1a) and X² is NR⁸;

Y is S or —CR^(2a)═CR^(2a)—;

X³, X⁴ and X⁵ are independently selected from C(R⁹) or N;

W is O or S;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one N, S or O as a hetero atom onthe ring, or a 6-membered heteroaryl ring containing at least onenitrogen atom,or alternately the moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy;

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R^(2a) is independently at each occurrence selected from the groupconsisting of H, halo, CN, C₁-C₃ alkyl, C₁₋₃ haloalkyl, C₁-C₃ alkoxy,and C₁-C₃ haloalkoxy;

R³ is selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₃-C₆ cycloalkyl,C₂-C₃ alkenyl, C₂-C₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁶ is selected from H, C₁-C₆ alkyl, C₁-C₃ haloalkyl, orC₁-C₃hydroxyalkyl; and

R⁷ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3hetero atoms independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, cycloalkyl, aryl,heterocylic and heteroaryl group is independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,haloalkyl, aryl, heteroaryl, alkoxy, haloalkoxy, aryloxy, arylalkyloxy,alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro,cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹,NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy, whereinR¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl or R¹⁰ andR¹¹ can be taken together with the N they are attached to to form a 4-7membered heterocycle ring;

-   -   or R⁶ and R⁷ may be taken together to form a monocyclic or        bicyclic heterocyclic ring with 0-2 additional heteroatoms        selected independently from N, O, or S, wherein each of said        monocyclic or bicyclic heterocylic ring can be independently        unsubstituted or substituted with 1-3 moieties which can be the        same or different and being independently selected from the        group consisting of halo, alkyl, aryl, heteroaryl, alkoxy,        aryloxy, arylalkyoxy, alkyloxycarbonyl, alkylcarboxy,        aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),        N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,        NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹²        and R¹³ are the same or different and are H or C₁₋₄ alkyl, or        R¹² and R¹³ can be taken together with the N they are attached        to to form a 4-7 membered heterocycle ring.

R⁸ is H or C₁-C₄ alkyl; and

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl, C₁₋₆haloalkyl, —C₁-C₆ alkoxy and C₁-C₃ haloalkoxy;

with the proviso that when Y is S and A is

then R⁷ is not pyridizin-4-yl.

In another embodiment, the present invention provides imidazopyridazineor imidazothiadiazole compounds, stereoisomers, tautomers, salts,solvates or prodrugs thereof, of Formula I having the structure:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

the dashed line represents an optional double-bond with the proviso thatonly one of the two dashed line double bonds exists at the same time;

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S; or

X¹ is N and X² is NR⁸; or

X¹ is NR⁸ and X² is N; or

X¹ is NR⁸ and X² is CR^(1a); or

X¹ is CR^(1a) and X² is NR⁸;

Y is S or —CR^(2a)═CR^(2a)—;

X³, X⁴ and X⁵ are independently selected from C(R⁹) or N;

W is O or S;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom,or alternately the moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy;

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R^(2a) is independently at each occurrence selected from the groupconsisting of H, halo, CN, C₁-C₃ alkyl, C₁₋₃ haloalkyl, C₁-C₃ alkoxy,and C₁-C₃ haloalkoxy;

R³ is selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₃-C₆ cycloalkyl,C₂-C₃ alkenyl, C₂-C₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁶ is selected from H, C₁-C₆ alkyl, C₁-C₃ haloalkyl, orC₁-C₃hydroxyalkyl; and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3hetero (ring) atoms independently selected from N, O or S, C₃₋₇cycloalkyl, and 6-10 membered heteroaryl, wherein each of said alkyl,cycloalkyl, aryl, heterocylic and heteroaryl group is independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, haloalkyl, aryl, heteroaryl, alkoxy, haloalkoxy, aryloxy,arylalkyloxy, alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl,arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹,SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹, NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, COOH, COOR¹⁰, oxo andmethylenedioxy, wherein R¹⁰ and R¹¹ are the same or different and are Hor C₁₋₄ alkyl or R¹⁰ and R¹¹ can be taken together with the N they areattached to to form a 4-7 membered heterocycle ring;

-   -   or R⁶ and R⁷ may be taken together to form a monocyclic or        bicyclic heterocyclic ring with 0-2 additional hetero (ring)        atoms selected independently from N, O, or S, wherein each of        said monocyclic or bicyclic heterocylic ring can be        independently unsubstituted or substituted with 1-3 moieties        which can be the same or different and being independently        selected from the group consisting of halo, alkyl, aryl,        heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,        alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH,        NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³,        NR¹²COR¹³, NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy,        wherein R¹² and R¹³ are the same or different and are H or C₁₋₄        alkyl, or R¹² and R¹³ can be taken together with the N they are        attached to to form a 4-7 membered heterocycle ring.

R⁸ is H or C₁-C₄ alkyl; and

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl, C₁₋₆haloalkyl, —C₁-C₆ alkoxy and C₁-C₃ haloalkoxy;

with the proviso that when Y is S and A is

then R⁷ is not pyridizin-4-yl.

The term “at least one nitrogen atom” in the definition of the moiety

means 1-3 nitrogen atoms.

In an embodiment,

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S.

In an embodiment, Y is S.

In an embodiment, Y is —CR^(2a)═CR^(2a)—, and both R^(2a) are H making Ythe moiety-CH═CH—. When Y is S, Formula I is Formula IA:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

the dashed line represents an optional double-bond with the proviso thatonly one of the two dashed line double bonds exists at the same time;

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S;

X³, X⁴ and X⁵ are independently selected from C(R⁹) or N;

W is O or S;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom,or alternately the moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy;

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R³ is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, C₃₋₆ cycloalkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁸ is H or C₁-C₄ alkyl;

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl,haloC₁₋₆ alkyl, —O—(C₁-C₆ alkyl) and haloC₁₋₃ alkoxy;

R⁶ is selected from H, C₁-C₆ alkyl, haloC₁₋₃alkyl, or hydroxyC₁₋₃alkyl;and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero (ring) atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring,

with the proviso that when A is

then R⁷ is not pyridizin-4-yl.

When Y is —CH═CH—, Formula I is Formula IB

wherein:

the dashed line represents an optional double-bond with the proviso thatonly one of the two dashed line double bonds exists at the same time;

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S;

X³, X⁴ and X⁵ are independently selected from C(R⁹) or N;

W is O or S;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom,or alternately the moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy;

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R³ is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, C₃₋₆ cycloalkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁸ is H or C₁-C₄ alkyl;

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl,haloC₁₋₆ alkyl, —O—(C₁-C₆ alkyl) and haloC₁₋₃ alkoxy;

R⁶ is selected from H, C₁-C₆ alkyl, haloC₁₋₃alkyl, or hydroxyC₁₋₃alkyl;and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero (ring) atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, COOH, COOR¹², oxo andmethylenedioxy, wherein R¹² and R¹³ are the same or different and are Hor C₁₋₄ alkyl or R¹² and R¹³ can be taken together with the N they areattached to to form a 4-7 membered heterocycle ring.

In another embodiment, the present invention provides imidazopyridazineor imidazothiadiazole compounds, stereoisomers, tautomers, salts,solvates or prodrugs thereof, of Formula:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

the dashed line represents an optional double-bond with the proviso thatonly one of the two dashed line double bonds exists at the same time;

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S; or

X¹ is N and X² is NR⁸; or

X¹ is NR and X² is N; or

X¹ is NR⁸ and X² is CR^(1a); or

X¹ is CR^(1a) and X² is NR⁸;

Y is S or —CR^(2a)═CR^(2a)—;

X³, X⁴ and X⁵ are independently selected from C(R⁹) or N;

W is O or S;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one N, S or O as a hetero atom onthe ring, or a 6-membered heteroaryl ring containing at least onenitrogen atom,

or alternately the moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy;

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R^(2a) is independently at each occurrence selected from the groupconsisting of H, halo, CN, C₁-C₃ alkyl, C₁₋₃ haloalkyl, C₁-C₃ alkoxy,and C₁-C₃ haloalkoxy;

R³ is selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₃-C₆ cycloalkyl,C₂-C₃ alkenyl, C₂-C₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁶ is selected from H, C₁-C₆ alkyl, C₁-C₃ haloalkyl, orC₁-C₃hydroxyalkyl; and

R⁷ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3hetero atoms independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, cycloalkyl, aryl,heterocylic and heteroaryl group is independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,haloalkyl, aryl, heteroaryl, alkoxy, haloalkoxy, aryloxy, arylalkyloxy,alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro,cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹,NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy, whereinR¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl or R¹⁰ andR¹¹ can be taken together with the N they are attached to to form a 4-7membered heterocycle ring;

-   -   or R⁶ and R⁷ may be taken together to form a monocyclic or        bicyclic heterocyclic ring with 0-2 additional heteroatoms        selected independently from N, O, or S, wherein each of said        monocyclic or bicyclic heterocylic ring can be independently        unsubstituted or substituted with 1-3 moieties which can be the        same or different and being independently selected from the        group consisting of halo, alkyl, aryl, heteroaryl, alkoxy,        aryloxy, arylalkyoxy, alkyloxycarbonyl, alkylcarboxy,        aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),        N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,        NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹²        and R¹³ are the same or different and are H or C₁₋₄ alkyl, or        R¹² and R¹³ can be taken together with the N they are attached        to to form a 4-7 membered heterocycle ring;

R⁸ is H or C₁-C₄ alkyl; and

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl, C₁₋₆haloalkyl, —C₁-C₆ alkoxy and C₁-C₃ haloalkoxy.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula IC:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

the dashed line represents an optional double-bond with the proviso thatonly one of the two dashed line double bonds exists at the same time;

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S;

W is O;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom,or alternately the moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy;

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R³ is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, C₃₋₆ cycloalkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁸ is H or C₁-C₄ alkyl;

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl,haloC₁₋₆ alkyl, —O—(C₁-C₆ alkyl) and haloC₁₋₃ alkoxy;

R⁶ is selected from H, C₁-C₆ alkyl, haloC₁₋₃alkyl, or hydroxyC₁₋₃alkyl;and

R⁷ is selected from the group consisting of C₂-C₆ alkyl, C₆-C₁₀ aryl,C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3 moietiesindependently selected from N, O or S, C₃₋₇ cycloalkyl, and 6-10membered heteroaryl, wherein each of said alkyl, aryl, heterocylic andheteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero (ring) atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula ID:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

the dashed line represents an optional double-bond with the proviso thatonly one of the two dashed line double bonds exists at the same time;

X¹ is O and X² is CR^(1a) or N; or

X¹ is N and X² is O; or

X¹ is N or CR^(1a), and X² is S;

W is O;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom,or alternately the moiety

is selected from

R^(1a) is selected from the group consisting of H, or methyl;

R² is H, or methyl;

R³ is selected from the group consisting of methyl, ethyl, methoxy,1,1-difluoroethyl, or 1-fluoroethyl;

R⁴ and R⁵ are independently selected from H or methyl;

R⁸ is H or methyl;

R⁹ is methoxy;

R⁶ is selected from H or methyl

R⁷ is selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ aryl,C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3 moietiesindependently selected from N, O or S, C₃₋₇ cycloalkyl, and 6-10membered heteroaryl, wherein each of said alkyl, aryl, heterocylic andheteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero (ring) atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring,

with the proviso that when A is

R⁷ is not pyridizin-4-yl.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds of Formula I are compounds of formulasIE, IF, IG, IH and IJ:

wherein the various moieties are independently selected and are asdefined earlier,with the proviso that when Y is S and A is

then R⁷ is not pyridizin-4-yl.

Examples of IE-IJ are:

with the proviso that when A is, R⁷ is not pyridizin-4-yl.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I are compoundsof formulas IN, IO, IP, IQ and IR:

Examples of IN-IR are:

wherein the various moieties are independently selected and are asdefined earlier. In an embodiment, in the compound of Formula I, themoiety:

represents the moiety:

wherein X³, X⁴ and X⁵ are as defined under Formula I.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I are compoundsof formula:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

W is O or S;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom,or alternately the moiety

is selected from

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R³ is selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₃-C₆ cycloalkyl,C₂-C₃ alkenyl, C₂-C₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁶ is selected from H, C₁-C₆ alkyl, C₁-C₃ haloalkyl, orC₁-C₃hydroxyalkyl; and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3hetero (ring) atoms independently selected from N, O or S, C₃₋₇cycloalkyl, and 6-10 membered heteroaryl, wherein each of said alkyl,cycloalkyl, aryl, heterocylic and heteroaryl group is independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, haloalkyl, aryl, heteroaryl, alkoxy, haloalkoxy, aryloxy,arylalkyloxy, alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl,arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹,SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹, NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, COOH, COOR¹⁰, oxo andmethylenedioxy, wherein R¹⁰ and R¹¹ are the same or different and are Hor C₁₋₄ alkyl or R¹⁰ and R¹¹ can be taken together with the N they areattached to to form a 4-7 membered heterocycle ring;

-   -   or R⁶ and R⁷ may be taken together to form a monocyclic or        bicyclic heterocyclic ring with 0-2 additional hetero (ring)        atoms selected independently from N, O, or S, wherein each of        said monocyclic or bicyclic heterocylic ring can be        independently unsubstituted or substituted with 1-3 moieties        which can be the same or different and being independently        selected from the group consisting of halo, alkyl, aryl,        heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,        alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH,        NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³,        NR¹²COR¹³, NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy,        wherein R¹² and R¹³ are the same or different and are H or C₁₋₄        alkyl or R¹² and R¹³ can be taken together with the N they are        attached to to form a 4-7 membered heterocycle ring; and

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl, C₁₋₆haloalkyl, —C₁-C₆ alkoxy and C₁-C₃ haloalkoxy,

with the proviso that when A is

R⁷ is not pyridizin-4-yl.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I are compoundsof formula:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

W is O or S;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom,or alternately the moiety

is selected from

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl;

R³ is selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₃-C₆ cycloalkyl,C₂-C₃ alkenyl, C₂-C₃ alkynyl and halo;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring;

R⁶ is selected from H, C₁-C₆ alkyl, C₁-C₃ haloalkyl, orC₁-C₃hydroxyalkyl; and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3hetero (ring) atoms independently selected from N, O or S, C₃₋₇cycloalkyl, and 6-10 membered heteroaryl, wherein each of said alkyl,cycloalkyl, aryl, heterocylic and heteroaryl group is independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, haloalkyl, aryl, heteroaryl, alkoxy, haloalkoxy, aryloxy,arylalkyloxy, alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl,arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹,SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹, NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, COOH, COOR¹⁰, oxo andmethylenedioxy, wherein R¹⁰ and R¹¹ are the same or different and are Hor C₁₋₄ alkyl or R¹⁰ and R¹¹ can be taken together with the N they areattached to to form a 4-7 membered heterocycle ring;

-   -   or R⁶ and R⁷ may be taken together to form a monocyclic or        bicyclic heterocyclic ring with 0-2 additional hetero (ring)        atoms selected independently from N, O, or S, wherein each of        said monocyclic or bicyclic heterocylic ring can be        independently unsubstituted or substituted with 1-3 moieties        which can be the same or different and being independently        selected from the group consisting of halo, alkyl, aryl,        heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,        alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH,        NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³,        NR¹²COR¹³, NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy,        wherein R¹² and R¹³ are the same or different and are H or C₁₋₄        alkyl or R¹² and R¹³ can be taken together with the N they are        attached to to form a 4-7 membered heterocycle ring; and

R⁹ is selected from the group consisting of H, halo, C₁-C₆ alkyl, C₁₋₆haloalkyl, —C₁-C₆ alkoxy and C_(1-C3) haloalkoxy.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IE, or they are compounds of Formula IF, orthey are compounds of Formula IG, or they are compounds of Formula IH,or they are compounds of Formula IJ, or they are compounds of FormulaIN, or they are compounds of Formula IO, or they are compounds ofFormula IP, or they are compounds of Formula IQ, or they are compoundsof Formula IR:

wherein the various moieties are independently selected and:

X³, and X⁵ are CH;

X⁴ is CR⁹;

W is O;

Y is S or —CH═CH—;

R^(1a) is H;

R² is H;

R³ is —OCH₃;

R⁴ and R⁵ are H;

R⁶ is H or methyl;

R⁹ is —OCH₃;

R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero (ring) atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IC, or they are compounds of Formula ID, orthey are compounds of Formula IE, or they are compounds of Formula IF,or they are compounds of Formula IG, or they are compounds of FormulaIH, or they are compounds of Formula IJ, or they are compounds ofFormula IN, or they are compounds of Formula IO, or they are compoundsof Formula IP, or they are compounds of Formula IQ, or they arecompounds of Formula IR:

wherein the various moieties are independently selected and:

X³═X⁵═CH;

X⁴ is CR⁹;

W is O;

Y is S;

R^(1a) is H;

R² is H;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is H;

R⁹ is methoxy;

R¹ is —N(R⁶)—C(O)—R⁷ or N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero (ring) atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IC, or they are compounds of Formula ID, orthey are compounds of Formula IE, or they are compounds of Formula IF,or they are compounds of Formula IG, or they are compounds of FormulaIH, or they are compounds of Formula IJ, or they are compounds ofFormula IN, or they are compounds of Formula IO, or they are compoundsof Formula IP, or they are compounds of Formula IQ, or they arecompounds of Formula IR:

wherein the various moieties are independently selected and:

X³═X⁵═CH;

X⁴ is CR⁹;

W is O;

Y is S;

R^(1a) is H;

R² is H or halo;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is H;

R⁹ is methoxy;

R¹ is —N(R⁶)—C(O)—R⁷ or;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;

or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero (ring) atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IC, or they are compounds of Formula ID, orthey are compounds of Formula IE, or they are compounds of Formula IF,or they are compounds of Formula IG, or they are compounds of FormulaIH, or they are compounds of Formula IJ, or they are compounds ofFormula IN, or they are compounds of Formula IO, or they are compoundsof Formula IP, or they are compounds of Formula IQ, or they arecompounds of Formula IR:

wherein the various moieties are independently selected and:

X³═CH;

X⁴═CR⁹;

X⁵ is N;

W is O;

Y is S;

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, and C₁-C₄ alkoxy;

R² is H;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is H;

R¹ is —N(R⁶)—C(O)—R⁷ or N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;

or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are C₁₋₄ alkyl or R¹⁰and R¹¹ can be taken together with the N they are attached to to form a4-7 membered heterocycle ring;

-   -   or R⁶ and R⁷ may be taken together to form a monocyclic or        bicyclic heterocyclic ring with 0-2 additional hetero atoms        selected independently from N, O, or S, wherein each of said        monocyclic or bicyclic heterocylic ring can be independently        unsubstituted or substituted with 1-3 moieties which can be the        same or different and being independently selected from the        group consisting of halo, alkyl, aryl, heteroaryl, alkoxy,        aryloxy, arylalkyoxy, alkyloxycarbonyl, alkylcarboxy,        aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),        N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,        NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹²        and R¹³ are the same or different and are C₁₋₄ alkyl or R¹² and        R¹³ can be taken together with the N they are attached to to        form a 4-7 membered heterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IC, or they are compounds of Formula ID, orthey are compounds of Formula IE, or they are compounds of Formula IF,or they are compounds of Formula IG, or they are compounds of FormulaIH, or they are compounds of Formula IJ, or they are compounds ofFormula IN, or they are compounds of Formula IO, or they are compoundsof Formula IP, or they are compounds of Formula IQ, or they arecompounds of Formula IR:

wherein the various moieties are independently selected and are:

X⁴═X⁵═CH;

X³ is N;

W is O;

Y is S;

R^(1a) is H;

R² is H or halo;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is H;

R⁹ is methoxy;

R¹ is —N(R⁶)—C(O)—R⁷ or;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;

or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IC, or they are compounds of Formula ID, orthey are compounds of Formula IE, or they are compounds of Formula IF,or they are compounds of Formula IG, or they are compounds of FormulaIH, or they are compounds of Formula IJ, or they are compounds ofFormula IN, or they are compounds of Formula IO, or they are compoundsof Formula IP, or they are compounds of Formula IQ, or they arecompounds of Formula IR:

wherein the various moieties are independently selected and:

X³═X⁴═CH;

X⁵ is N;

W is O;

Y is S;

R^(1a) is H;

R² is H or halo;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is H;

R⁹ is methoxy;

R¹ is —N(R⁶)—C(O)—R⁷ or;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;

or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IC, or they are compounds of Formula ID, orthey are compounds of Formula IE, or they are compounds of Formula IF,or they are compounds of Formula IG, or they are compounds of FormulaIH, or they are compounds of Formula IJ, or they are compounds ofFormula IN, or they are compounds of Formula IO, or they are compoundsof Formula IP, or they are compounds of Formula IQ, or they arecompounds of Formula IR:

wherein the various moieties are independently selected and:

X⁴═X⁵═CH;

X³ is N;

W is O;

Y is S;

R^(1a) is H;

R² is H or halo;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is H;

R⁹ is methoxy;

R¹ is —N(R⁶)—C(O)—R⁷ or;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of C₂-C₆ alkyl, C₆-C₁₀ aryl,C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3 moietiesindependently selected from N, O or S, C₃₋₇ cycloalkyl, and 6-10membered heteroaryl, wherein each of said alkyl, aryl, heterocylic andheteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula IA, or they are compounds of Formula IB, or theyare compounds of Formula IC, or they are compounds of Formula ID, orthey are compounds of Formula IE, or they are compounds of Formula IF,or they are compounds of Formula IG, or they are compounds of FormulaIH, or they are compounds of Formula IJ, or they are compounds ofFormula IN, or they are compounds of Formula IO, or they are compoundsof Formula IP, or they are compounds of Formula IQ, or they arecompounds of Formula IR:

wherein the various moieties are independently selected and:

X³═X⁴═X⁵═CH;

W is O;

Y is S;

R^(1a) is H;

R² is H or halo;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is H;

R⁹ is methoxy;

R¹ is —N(R⁶)—C(O)—R⁷ or;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom;

or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl orR¹⁰ and R¹¹ can be taken together with the N they are attached to toform a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl or R¹² and R¹³ can betaken together with the N they are attached to to form a 4-7 memberedheterocycle ring.

In another embodiment,

is a phenyl ring;or alternately the moiety

is selected from or

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds of Formula I are compounds of formula:

wherein the various moieties are independently selected and:

W is O;

R² is H;

R³ is CH₃ or methoxy;

R⁴ and R⁵ are H;

R⁶ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or arylalkyl;

R¹ is —N(R⁶)—C(O)—R⁷ or N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring;

or alternately the moiety

is selected from

and

R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹, COOH, COOR¹⁰, oxo andmethylenedioxy, wherein R¹⁰ and R¹¹ are the same or different and areC₁₋₄ alkyl or R¹⁰ and R¹¹ can be taken together with the N they areattached to to form a 4-7 membered heterocycle ring;

or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are C₁₋₄ alkyl or R¹² and R¹³ can be takentogether with the N they are attached to to form a 4-7 memberedheterocycle ring, with the proviso that when A is

then R⁷ is not pyridizin-4-yl.

In yet another embodiment, this invention discloses the compounds listedin Table 1.

TABLE 1 Compound

In one embodiment, the present invention provides N compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula I.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IA.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IA.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IB.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IC.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula ID.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IE.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IF.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IG.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IH.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IJ.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IN.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IO.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IP.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IQ.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IR.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are the examples.

PAR4 compounds of the invention have IC₅₀s in the FLIPR Assay (describedhereinafter) of about 10 μM, or 5 μM or less, or 500 nM or less, or 10nM or less. Activity data for Examples 1-166 are presented in the tablesof Example E.

In some embodiments, the present invention provides at least onecompound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug ester thereof.

In some embodiments, the present invention provides one or morecompounds of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug ester thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition, which includes a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one compound of Formula I,or Formula IA, or Formula IB, or Formula IC, or Formula ID, or FormulaIE, or Formula IF, or Formula IG, or Formula IH, or Formula IJ, FormulaIN, or Formula IO, or Formula IP, or Formula IQ, or Formula IR, orpreferably, a compound selected from one of the examples, morepreferably, Examples 1 to 166, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,alone or in combination with another therapeutic agent.

In some embodiments, the present invention provides a pharmaceuticalcomposition which includes a therapeutically effective amount of atleast one compound of Formula I, or Formula IA, or Formula IB, orFormula IC, or Formula ID, or Formula IE, or Formula IF, or Formula IG,or Formula IH, or Formula IJ, or Formula IN, or Formula IO, or FormulaIP, or Formula IQ, or Formula IR, or and one or more additionaltherapeutic agent(s). In a preferred embodiment, the present inventionprovides a pharmaceutical composition, wherein the additionaltherapeutic agent(s) are an anti-platelet agent or a combinationthereof. Preferably, the anti-platelet agent(s) are P2Y12 antagonistsand/or aspirin. Preferably, the P2Y12 antagonists are clopidogrel,ticagrelor, or prasugrel. In another preferred embodiment, the presentinvention provides a pharmaceutical composition, wherein the additionaltherapeutic agent(s) are an anticoagulant or a combination thereof.Preferably, the anticoagulant agent(s) are FXa inhibitors or thrombininhibitors. Preferably, the FXa inhibitors are apixaban or rivaroxaban.Preferably, the thrombin inhibitor is dabigatran.

In some embodiments, the present invention provides a method for thetreatment or prophylaxis of a thromboembolic disorder which includes thestep of administering to a subject (for example, a human) in need ofsuch treatment or prophylaxis a therapeutically effective amount of atleast one compound of Formula I, or Formula IA, or Formula IB, orFormula IC, or Formula ID, or Formula IE, or Formula IF, or Formula IG,or Formula IH, or Formula IJ, or Formula IN, or Formula IO, or FormulaIP, or Formula IQ, or Formula IR, or of the Examples herein orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrug esters thereof.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of one compound of Formula I, orFormula IA, or Formula IB, or Formula IC, or Formula ID, or Formula IE,or Formula IF, or Formula IG, or Formula IH, or Formula IJ, Formula IN,or Formula IO, or Formula IP, or Formula IQ, or Formula IR, or acompound selected from one of the examples, more preferably, Examples 1to 166, or stereoisomers, tautomers, pharmaceutically acceptable salts,prodrug esters, or solvates thereof, wherein the thromboembolic disorderis selected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of one compound of Formula I, orFormula IA, or Formula IB, or Formula IC, or Formula ID, or Formula IE,or Formula IF, or Formula IG, or Formula IH, or Formula IJ, Formula IN,or Formula IO, or Formula IP, or Formula IQ, or Formula IR, or acompound selected from one of the examples, more preferably, Examples 1to 166, or stereoisomers, tautomers, pharmaceutically acceptable salts,prodrug esters, or solvates thereof, wherein the thromboembolic disorderis selected from the group consisting of acute coronary syndrome,unstable angina, stable angina, ST-elevated myocardial infarction,non-ST-elevated myocardial infarction, atrial fibrillation, myocardialinfarction, transient ischemic attack, stroke, atherosclerosis,peripheral arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, cancer-related thrombosis, and thrombosis resultingfrom medical implants, devices, and procedures in which blood is exposedto an artificial surface that promotes thrombosis.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of one compound of Formula I, orFormula IA, or Formula IB, or Formula IC, or Formula ID, or Formula IE,or Formula IF, or Formula IG, or Formula IH, or Formula IJ, Formula IN,or Formula IO, or Formula IP, or Formula IQ, or Formula IR, or acompound selected from one of the examples, more preferably, Examples 1to 166, or stereoisomers, tautomers, pharmaceutically acceptable salts,prodrug esters, or solvates thereof, wherein the thromboembolic disorderis selected from the group consisting of acute coronary syndrome,unstable angina, stable angina, ST-elevated myocardial infarction, andnon-ST-elevated myocardial infarction.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of one compound of Formula I, orFormula IA, or Formula IB, or Formula IC, or Formula ID, or Formula IE,or Formula IF, or Formula IG, or Formula IH, or Formula IJ, Formula IN,or Formula IO, or Formula IP, or Formula IQ, or Formula IR, or or acompound selected from one of the examples, more preferably, Examples 1to 166, or stereoisomers, tautomers, pharmaceutically acceptable salts,prodrug esters, or solvates thereof, wherein the thromboembolic disorderis selected from the group consisting of transient ischemic attack andstroke.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of one compound of Formula I, orFormula IA, or Formula IB, or Formula IC, or Formula ID, or Formula IE,or Formula IF, or Formula IG, or Formula IH, or Formula IJ, Formula IN,or Formula IO, or Formula IP, or Formula IQ, or Formula IR, or or acompound selected from one of the examples, more preferably, Examples 1to 166, or stereoisomers, tautomers, pharmaceutically acceptable salts,prodrug esters, or solvates thereof, wherein the thromboembolic disorderis peripheral arterial disease.

In some embodiments, the present invention includes a method asdescribed above wherein the thromboembolic disorder is selected fromunstable angina, an acute coronary syndrome, atrial fibrillation, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In some embodiments, the present invention includes a method ofinhibiting or preventing platelet aggregation, which includes the stepof administering to a subject (such as a human) in need thereof atherapeutically effective amount of a PAR4 antagonist, which is acompound of Formula I, or Formula IA, or Formula IB, or Formula IC, orFormula ID, or Formula IE, or Formula IF, or Formula IG, or Formula IH,or Formula IJ, Formula IN, or Formula IO, or Formula IP, or Formula IQ,or Formula IR, or or a compound selected from one of the examples, morepreferably, Examples 1 to 166, of the invention.

Other Embodiments of the Invention

In some embodiments, the present invention provides a process for makingthe compounds of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug ester thereof.

In some embodiments, the present invention provides an intermediate formaking the compounds of the present invention or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate or prodrug esterthereof.

In some embodiments, the invention provides a method of treatment orprophylaxis of a thromboembolic disorder involving administering to asubject in need thereof (e.g., a human) a therapeutically effectiveamount of at least one compound that binds to PAR4 (such as a compoundof Formula I of the invention) and inhibits PAR4 cleavage and/orsignaling, wherein said subject has a dual PAR1/PAR4 platelet receptorrepertoire.

In some embodiments, the present invention provides a compound of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrug esters thereof, for use intherapy for the treatment or prophylaxis of a thromboembolic disorder.

In some embodiments, the present invention also provides the use of acompound of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrug esters thereof,for the manufacture of a medicament for the treatment or prophylaxis ofa thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Chemistry

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis- andtrans-geometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated. When nospecific mention is made of the configuration (cis, trans or R or S) ofa compound (or of an asymmetric carbon), then any one of the isomers ora mixture of more than one isomer is intended. The processes forpreparation can use racemates, enantiomers, or diastereomers as startingmaterials. All processes used to prepare compounds of the presentinvention and intermediates made therein are considered to be part ofthe present invention. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatography or fractional crystallization. Compounds of the presentinvention, and salts thereof, may exist in multiple tautomeric forms, inwhich hydrogen atoms are transposed to other parts of the molecules andthe chemical bonds between the atoms of the molecules are consequentlyrearranged. It should be understood that all tautomeric forms, insofaras they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene”, alone or as part ofanother group, is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having from 1 to 10 carbons orthe specified number of carbon atoms. For example, “C₁₋₁₀ alkyl” (oralkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉,and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl” denotesalkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted orsubstituted with at least one hydrogen being replaced by anotherchemical group. Example alkyl groups include, but are not limited to,methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl(e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl,isopentyl, neopentyl), as well as chain isomers thereof, and the like.“Alkenyl” or “alkenylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon double bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkenyl”(or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenylgroups. Examples of alkenyl include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, and 4-methyl-3-pentenyl, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonyl-amino, nitro, cyano, thiol, and/or alkylthio.

“Alkynyl” or “alkynylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon triple bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkynyl,(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy”, alone or as part of another group,refers to an —O-alkyl group, where alkyl is as defined above. “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.Similarly, “alkylthio” or “thioalkoxy”, alone or as part of anothergroup, represents an alkyl group or alkoxy group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example methyl-S— and ethyl-S—.

“Halo” or “halogen”, alone or as part of another group, includes fluoro,chloro, bromo, and iodo.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with at least 1 halogen up to fullysubstituted with halogens (perhaloalkyl), alternatively 1 to 7 halogens,or 1 to 4 halogens, preferably F and/or Cl. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,1,1-difluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl,heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl alsoinclude “fluoroalkyl” that is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 to 7 fluorineatoms, preferably 1 to 4 fluorine atoms.

“Halo-C₁-C₂-alkoxy” or “haloalkyloxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl), and tricyclic alkyl, containing a total of 3 to 10carbons forming the ring (C₃-C₁₀ cycloalkyl), and which may be fused to1 or 2 aromatic rings as described for aryl, which includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, cyclohexenyl, norbornyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl, as well as such groups including 2free bonds and thus are linking groups.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Preferred carbocycles, unless otherwise specified, are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term“carbocycle” is used, it is intended to include “aryl”. A bridged ringoccurs when one or more carbon atoms link two non-adjacent carbon atoms.Preferred bridges are one or two carbon atoms. It is noted that a bridgealways converts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.Unless otherwise specified, “aryl”, “C₆₋₁₀ aryl” or “aromatic residue”may be unsubstituted or substituted with 1 to 3 groups selected from OH,C₁-C₃ alkoxy, heterocyclyl, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H,N(CH₃)₂, CF₃, OCF₃, OCHF₂, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃,S(═O)₂NH₂, C₁-C₃ alkyl, CO₂H, and CO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclo” “heterocyclic” or“heterocyclyl” group is intended to mean a stable 4- to 14-memberedmonocyclic, bicyclic or tricyclic heterocyclic ring which is saturatedor partially unsaturated and which consists of carbon atoms and 1, 2, 3,or 4 heteroatoms independently selected from the group consisting of N,NH, O and S and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N—Oand S(O)_(p), wherein p is 0, 1 or 2). The nitrogen atom may besubstituted or unsubstituted (i.e., N or NR wherein R is H or anothersubstituent, if defined). The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure. The heterocyclic rings described herein may optionally besubstituted on carbon or on a nitrogen atom if the resulting compound isstable, with 1 to 3 groups selected from OH, OC₁-C₃ alkoxy, Cl, F, Br,I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, OCHF₂, ═O, C(═O)CH₃, SCH₃,S(═O)CH₃, S(═O)₂CH₃, S(═O)₂NH₂, C₁-C₃ alkyl, CO₂H and CO₂CH₃. A nitrogenin the heterocycle may optionally be quaternized. The heterocycle mayoptionally contain a ═O. It is preferred that when the total number of Sand O atoms in the heterocycle exceeds 1, then these heteroatoms are notadjacent to one another. It is preferred that the total number of S andO atoms in the heterocycle is not more than 1. Spiro and bridged ringsare also included in the definition of heterocycle. A bridged ringoccurs when one or more atoms (i.e., C, O, N, or S) link twonon-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge. When the term “heterocycle” is used, itis not intended to include heteroaryl.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, and the like.

Exemplary bicyclic heterocyclo groups include quinuclidinyl.

Preferred heterocyclo groups include

which optionally may be substituted.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are unsubstitutedor substituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2). Bridged rings are also included inthe definition of heteroaryl. A bridged ring occurs when one or moreatoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogenatoms. Examples of bridged rings include, but are not limited to, onecarbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms,and a carbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

Heteroaryl groups include, but are not limited to,

and the like.

When the term “unsaturated” is used herein to refer to a ring or group,which group may be fully unsaturated or partially unsaturated.

The term “acyl” alone or as part of another group refers to a carbonylgroup linked to an organic radical, more particularly, the groupC(═O)R_(e), as well as the bivalent groups —C(═O)— or —C(═O)R_(e)—,which are linked to organic radicals. The group R_(e) can be selectedfrom alkyl, alkenyl, alkynyl, aminoalkyl, substituted alkyl, substitutedalkenyl, or substituted alkynyl, as defined herein, or when appropriate,the corresponding bivalent group, e.g., alkylene, alkenylene, and thelike.

The designation “

” or

attached to a ring or other group refers to a free bond or linkinggroup.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

The term “at least one” or “one or more” is used to represent one, orsuitable multiples thereof such as, for example, two, three, four, five,six and the like.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

When a group or moiety in a structure appears to be short on valence,the remaining valences are understood to be filled with hydrogen atomsunless otherwise stated, e.g. (e.g., —N should be considered —NH or —NH₂and —O should be considered —OH, as needed, unless otherwise stated).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative. In cases in which there are quaternary carbonatoms in compounds of the present invention, these can be replaced bysilicon atoms, provided they do not form Si—N or Si—O bonds.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0 to 3 R^(3a), then said group mayoptionally be substituted with up to three R^(3a) groups, and at eachoccurrence R^(3a) is selected independently from the definition ofR^(3a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, L. V., Jr.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985); b) Bundgaard, H., Chapter 5, “Design and Application ofProdrugs”, Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Designand Development, pp. 113-191, Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

f) Rautio, J (Editor). Prodrugs and Targeted Delivery (Methods andPrinciples in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C. G., ed., The Practice of MedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

Isotopically labeled compounds of the present invention, i.e., whereinone or more of the atoms described are replaced by an isotope of thatatom (e.g., ¹²C replaced by ¹³C or by ¹⁴C; and isotopes of hydrogenincluding tritium and deuterium), are also provided herein. Suchcompounds have a variety of potential uses, e.g., as standards andreagents in determining the ability of a potential pharmaceuticalcompound to bind to target proteins or receptors, or for imagingcompounds of this invention bound to biological receptors in vivo or invitro.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 98%, preferably 99%, compoundof the present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates include, butare not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “cone.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “MS” or “Mass Spec” for mass spectrometry, “ESI”for electrospray ionization mass spectroscopy, “HR” for high resolution,“HRMS” for high resolution mass spectrometry, “LCMS” for liquidchromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” for thin layerchromatography, “SM” for starting material, “NMR” for nuclear magneticresonance spectroscopy, “¹H” for proton, “6” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “tlc” for thin layer chromatography.“α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designationsfamiliar to one skilled in the art.

Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl i-Bu isobutyl t-Butert-butyl Ph phenyl Bn benzyl AcOH acetic acid MeOH methanol EtOHethanol EtOAc ethyl acetate Et₂O diethyl ether i-PrOH or IPA isopropanolHOAc acetic acid BOP reagentbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateBBr₃ boron tribromide Boc tert-butyloxycarbonyl cDNA complimentary DNACDCl₃ deuterated chloroform CH₂Cl₂ dichloromethane CH₃CN acetonitrileACN acetonitrile DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2dichloroethane DCM dichloromethane DCC dicyclohexylcarbodiimide DIADdiisopropyl azodicarboxylate DIEA or N,N-diisopropylethylamine DIPEA DME1,2-dimethoxyethane DMF dimethyl formamide DMAPN,N-dimethylaminopyridine DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide EDC (or 3-ethyl-3′-(dimethylamino)propyl-carbodiimideEDC•HCl) hydrochloride or EDCI (or or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDCI•HCl) hydrochloride orEDAC EDTA ethylenediaminetetraacetic acid HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HCl hydrochloric acid HEPES4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid Hex hexane HOBt or1-hydroxybenzotriazole monohydrate HOBT Hunig's baseN,N-diisopropylethyl amine LAH lithium aluminum hydride LDA Lithiumdiisopropylamide LiHMDS Lithium bis(trimethylsilyl) amide mCPBA ormeta-chloroperbenzoic acid m-CPBA NMM N-methylmorpholine Pd/C palladiumon carbon PPA polyphosphoric acid PS polystyrene PXPd2 bis[di-tert-butylphosphinous chloride-kP]di-m- chlorodichloro dipalladium PyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TEAtriethylamine TFA trifluoroacetic acid THF tetrahydrofuran TRIStris(hydroxymethyl)aminomethane KOAc potassium acetate K₃PO₄ potassiumphosphate MgSO₄ magnesium sulfate NaCl sodium chloride NaH sodiumhydride NaHCO₃ sodium bicarbonate NaOH sodium hydroxide Na₂SO₃ sodiumsulfite Na₂SO₄ sodium sulfate NH₃ ammonia NH₄Cl ammonium chloride NH₄OHammonium hydroxide OTs tosylate, para-toluenesulfonate PBr₃ phosphoroustribromide Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium (0) (S,S)-(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene EtDuPhosRh(I)(cyclooctadiene)rhodium (I) trifluoromethanesulfonate

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Wuts et al. (Greene's Protective Groups In OrganicSynthesis, 4th Edition, Wiley-Interscience (2006)).

General Methods

The following methods were used in the exemplified Examples, exceptwhere noted otherwise.

HPLC Methods:

Method A: Column Zorbax XDB-C18 3.5 microns, 4.6×30 mm; Mobile Phase:A=MeOH:H₂O:TFA (95:5:05), B=MeOH:H₂O:TFA (5:95:05). Grad.: T=0: 100%solv A; T=2:100% solv B; stop time: 4 min. Flow=3.0 mL/minMethod B: Agilent Poroshell 120; EC-C18, 2.7 um; 2.1×30 mm; MobilePhase: Solv A: 5% MeOH: 95% H2O+0.1% AcOH; Solv B: 95% MeOH: 5% H2O+0.1%AcOH; Grad.: T=0: 100% solv A; T=1:100% solv B; stop time: 4 min.Flow=1.0 mL/minMethod C: SunfireC18 3.5 microns column (4.6×30 mm) eluted at 3 mL/minwith a 2 min. gradient from 100% A to 100% B (A: 5% methanol, 94.95%water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220 nm)Method D: Eclipse XDB-C18 3.5 microns column (4.6×30 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% methanol,94.95% water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220nm)Method E: Eclipse XDB-C18 3.5 microns column (4.6×30 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% acetonitrile,94.95% water, 0.05% TFA; B: 5% water, 94.95% acetonitrile, 0.05% TFA, UV220 nm)Method F: Zorbax SB-Phenyl 3.5 microns column (4.6×50 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% methanol,94.95% water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220nm).

Example 1N-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)benzamide

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(0.050 g, 0.157 mmol, see WO13163279, WO13163241, and WO13163244 forpreparation of this compound and related intermediates where R³ and Y inFormula I are modified), triphenylphosphine (0.083 g, 0.316 mmol) andN-(3-(hydroxymethyl)phenyl)benzamide (0.072 g, 0.316 mmol) (J. L. Kellyand B. R. Baker, J. Med. Chem., 1982, 25, 600) in a 50 ml flask wasmaintained under vacuum for 10 min and then purged with nitrogen. Drytetrahydrofuran (4 ml) was added and the resulting heterogeneous mixturewas treated at 22° C. with a solution of diisopropyl azodicarboxylate(0.064 g, 0.316 mmol) in tetrahydrofuran (2 ml) added drop-wise over 10min. The resulting homogeneous solution was then stirred at 22° C. for 3h. The reaction mixture was quenched by the addition of dichloromethaneand saturated sodium bicarbonate. The organic phase was washed withbrine, dried over anhydrous magnesium sulfate and concentrated in vacuo.Chromatography of the residue on silica gel (elutiondichloromethane-ethyl acetate 5-10%) followed by crystallization fromethyl acetate gave 0.047 g (56% yield) of the title material as a whitesolid. HPLC (Method A): 2.348 min. HRMS (ESI) calcd for C₂₈H₂₃N₄O₅S[M+H]⁺ m/z 527.1384, found 527.142. ¹H NMR (CDCl₃, 400 MHz) δ ppm:7.85-7.90 (m, 2H), 7.84 (br. s, 1H), 7.82 (s, 1H), 7.74 (br. d, J=8.4Hz, 1H), 7.63 (br. s, 1H), 7.45-7.55 (m, 3H), 7.39 (t, J=7.8 Hz, 1H),7.25 (overlapping with CHCl₃, 1H), 7.09 (s, 1H), 6.67 (br. s, 1H), 6.36(br. s, 1H), 5.18 (s, 2H), 4.18 (s, 3H), 3.81 (s, 3H).

Example 24-Fluoro-N-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)benzamide

Reaction of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(0.080 g, 0.252 mmol) with 4-fluoro-N-(3-(hydroxymethyl)phenyl)benzamide(0.092 g, 0.378 mmol) as described in example 1 gave 0.099 g (72% yield)of the title material as a white solid. HPLC (Method A): 2.371 min. HRMS(ESI) calcd for C₂₈H₂₂FN₄O₅S [M+H]⁺ m/z 545.1289, found 545.1301. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.89-7.92 (m, 3H), 7.82 (s, 1H), 7.76 (br.d,J=7.9 Hz, 1H), 7.61 (s, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.23 (overlappingwith CHCl₃, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.09 (s, 1H), 6.67 (br. d, 1H),6.36 (d, J=1.7 Hz, 1H), 5.18 (s, 2H), 4.19 (s, 3H), 3.82 (s, 3H).

Example 3 tert-Butyl(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)carbamate

tert-Butyl (3-(hydroxymethyl)phenyl)carbamate

A mixture of 3-aminobenzyl alcohol (1.365 g, 11.08 mmol) in drytetrahydrofuran (15 mL) was treated at 23° C. with di-tert-butyldicarbonate (2.53 g, 11.59 mmol) and the resulting mixture was stirredfor 72 hours (the mixture became homogeneous after 5 min). The reactionmixture was then concentrated under reduced pressure and the oilyresidue was chromatography on silica gel (elution toluene-ethyl acetate8:2) to give 2.48 g (100% yield) of the title material as a thick syrupwhich crystallized to a white solid in the fridge. HPLC (Method A):1.715 min. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.43 (br. s, 1H), 7.26 (t,J=7.9 Hz, 1H), 7.20 (br. d, J=8.0 Hz, 1H), 7.02 (br. d, J=7.5 Hz, 1H),6.49 (br. s, 1H), 4.65 (d, J=6.0 Hz, 2H), 1.76 (t, J=6.0 Hz, 1H), 1.51(s, 9H).

tert-Butyl(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)carbamate

A suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(2.25 g, 7.09 mmol), tert-butyl (3-(hydroxymethyl)phenyl)carbamate (1.90g, 8.51 mmol) and triphenylphosphine (2.79 g, 10.63 mmol) in drytetrahydrofuran (150 mL) was treated at 22° C. and under nitrogen with asolution of diisopropyl azodicarboxylate (2.15 g, 10.63 mmol) intetrahydrofuran (20 ml) added drop-wise over 2 hours. The heterogeneousmixture was homogeneous at the end of the addition and was stirred foranother 3 hours. The reaction mixture was then quenched by the additionof ethyl acetate (400 mL) and saturated sodium bicarbonate. The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. Chromatography of the residue on silica gel(elution toluene-ethyl acetate 9:1) followed by crystallization fromethyl acetate gave 2.595 g (70% yield) of the title material ascolorless prisms. HPLC (Method A): 2.413 min. HRMS (ESI) calcd forC₂₆H₂₇N₄O₆S [M+H]⁺ m/z 523.1646, found 523.1676. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 7.83 (s, 1H), 7.42 (br. s, 1H), 7.38 (br. d, J=8 Hz, 1H), 7.30(t, J=8 Hz, 1H), 7.13 (br. d, J=7.6 Hz, 1H), 7.08 (s, 1H), 6.67 (br. d,1H),), 6.51 (br. s, 1H), 6.35 (d, J=1.9 Hz, 1H), 5.14 (s, 2H), 4.19 (s,3H), 3.82 (s, 3H), 1.51 (s, 9H).

Example 43-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)aniline

A solution of tert-butyl(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)carbamate(2.58 g, 4.93 mmol) in dichloromethane (150 mL) was treated at 22° C.and under nitrogen with trifluoroacetic acid (15 mL) added drop-wiseover 5 min. After 2 hours, the solvent and excess reagent wereevaporated under reduced pressure and the residue was partitionedbetween dichloromethane and saturated sodium bicarbonate. The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give a white solid. Triturationof this solid in a small amount of 1,2-dichloroethane followed byfiltration gave 1.74 g (83% yield) of the title aniline as a whitesolid. HPLC (Method A): 1.991 min. HRMS (ESI) calcd for C₂₁H₁₉N₄O₄S[M+H]m/z 423.1122, found 423.1129. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.30(s, 1H), 6.96 (t, J=7.7 Hz, 1H), 6.89 (s, 1H), 6.73 (br. d, 1H), 6.62(t, J=1.9 Hz, 1H), 6.53 (br. d, J=7.9 Hz, 1H), 6.43-6.45 (m, 1H), 6.40(d, J=1.9 Hz, 1H), 5.07 (br. s, 2H), 5.01 (s, 2H), 4.13 (s, 3H), 3.71(s, 3H).

Example 54-Chloro-N-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)benzamide

A solution of3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)aniline(0.058 g, 0.137 mmol) in dry tetrahydrofuran (4 mL) was treated at 22°C. and under nitrogen with 4-methylmorpholine (0.031 g, 0.3 mmol)followed by a solution of 4-chlorobenzoyl chloride (0.035 g, 0.20 mmol)in dry tetrahydrofuran (2 mL) added drop-wise over 2 min. After 1 hour,the reaction mixture was diluted with dichloromethane, washedsuccessively with cold 0.1N hydrochloric acid, saturated sodiumbicarbonate and brine. After drying over anhydrous magnesium sulfate,the organic phase was concentrated under reduced pressure.Chromatography of the residue on silica gel (elutiondichloromethane-ethyl acetate 9:1) followed by crystallization fromethyl acetate gave 0.046 g (60% yield) of the title material as a whitesolid. HPLC (Method A): 2.428 min. HRMS (ESI) calcd for C₂₈H₂₂ClN₄O₅S[M+H]+m/z 561.0994, found 561.1023. ¹H NMR (CDCl₃, 400 MHz) δ ppm:7.80-7.85 (m, 4H), 7.74 (br. d, J=8.6 Hz, 1H), 7.60 (br. s, 1H), 7.45(d, J=8.6 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.24 (overlapping with CHCl₃,1H), 7.09 (s, 1H), 6.67 (br. d, 1H), 6.35 (d, J=1.42 Hz, 1H), 5.18 (s,2H), 4.18 (s, 3H), 3.81 (s, 3H).

Example 6N-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)-3-(trifluoromethoxy)benzamide

Reaction of3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)aniline(0.056 g, 0.132 mmol) with 3-(trifluoromethoxy)benzoyl chloride (0.040g, 0.178 mmol) as described in example 5 gave 0.070 g (85% yield) of thetitle material as a white solid. HPLC (Method A): 2.437 min. HRMS (ESI)calcd for C₂₉H₂₂F₃N₄O₆S [M+H]⁺ m/z 611.1207, found 611.1186. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.85 (s, 1H), 7.81 (s, 1H), 7.77 (d, J=7.7 Hz,1H), 7.71-7.75 (m, 2H), 7.62 (s, 1H), 7.50 (t, J=8 Hz, 2H), 7.37-7.41(m, 2H), 7.26 (overlapping with CHCl₃, 1H), 6.66 (br. d, 1H), 6.35 (d,J=1.87 Hz, 1H), 5.17 (s, 2H), 4.18 (s, 3H), 3.81 (s, 3H).

Example 7N-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)benzenesulfonamide

Reaction of3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)aniline(0.200 g, 0.473 mmol) with benzenesulfonyl chloride (0.125 g, 0.71 mmol)as described in example 5 gave 0.206 g (77% yield) of the title materialas a white solid. HPLC (Method A): 2.28 min. HRMS (ESI) calcd forC₂₇H₂₃N₄O₆S₂ [M+H]⁺ m/z 563.1054, found 563.1045. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 10.34 (s, 1H), 8.35 (s, 1H), 7.69-7.71 (m, 2H), 7.53-7.57(m, 1H), 7.44-7.48 (m, 2H), 7.25 (s, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.09(d, J=7.8 Hz, 1H), 6.99-7.02 (m, 1H), 6.91 (s, 1H), 6.78 (br. d, 1H),6.40 (d, J=1.84 Hz, 1H), 5.17 (s, 2H), 4.17 (s, 3H), 3.74 (s, 3H).

Library Approach with Aniline Described in Example 4

In a 4 mL vial was weighted the3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)aniline(0.025 g, 0.059 mmol). Dry tetrahydrofuran (1 mL) was added, followed by4-methylmorpholine (25 μL, 0.22 mmol, ˜3.7 equivalent). Then the acidchloride (0.082 mmol, 1.4 equivalent) in tetrahydrofuran (0.5 mL) wasadded all at once. The resulting mixture was stirred on a HeidolphUnimax 1010 shaker (300 rpm) for 2 h. HPLC indicated completedisappearance of the starting aniline. The reaction mixture was thenquenched by the addition of water (0.5 mL) and acetic acid (two drops,the solution became homogeneous). The reaction mixture is directlypurified by prep HPLC (Zorbax SB-C18 Prep HT 5 um; 21.2×100 mm; solventA MeOH:H2O/TFA 0.05% (5:95), solvent B MeOH:H2O/TFA 0.05% (95:5), T 0-2min: 40% solvent B; 8 min gradient to 100% solvent B; stop time 15 min.;220 nm). The selected fractions are concentrated and the residue waslyophilized from an acetonitrile-water mixture to give ˜15-30 mg of theamide as a white solid.

Calc. LCMS HPLC Retention [M + H]⁺ [M + H]⁺ Ex. Structure Formula Time(Min)/Method m/z m/z NMR 8

C₃₀H₂₄N₄O₇S 2.273/A 585.1438 585.1432 ¹H NMR (CDCl₃) δ ppm: 8.06 (s,1H), 7.85 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.62-7.66 (m, 2H), 7.48-7.52 (m, 1H), 7.33-7.40 (m, 2H), 7.25-7.27 (m, 1H), 7.13-7.15 (m, 2H),6.66 (br. d, 1H), 6.36 (d, J = 1.9 Hz, 1H), 5.20 (s, 2H), 4.21 (s, 3H),3.81 (s, 3H), 2.28 (s, 3H). 9

C₃₀H₂₀F₆N₄O₅S 2.373/A 663.1131 663.1132 ¹H NMR (CDCl₃) δ ppm: 7.86 (s,1H), 7.83 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H),7.69 (dd, J = 8.4, 1.3 Hz, 1H), 7.58 (s, 2H), 7.53 (s, 1H), 7.33-7.37(m, 1H), 7.21 (d, J = 1.85 Hz, 1H), 7.09 (s, 1H), 6.60 (br. d, 1H), 6.31(d, J = 1.85 Hz, 1H), 5.13 (s, 2H), 4.14 (s, 3H), 3.76 (s, 3H). 10

C₂₈H₂₁BrN₄O₅S 2.438/A 605.0489 605.0475 ¹H NMR (CDCl₃) δ ppm: 8.01 (br.s, 1H), 7.82 (s, 1H), 7.81 (br. s, 1H), 7.77-7.80 (m, 1H), 7.71- 7.74(m, 1H), 7.65-7.67 (m, 1H), 7.63 (br. s, 1H), 7.40 (t, J = 7.9 Hz, 1H),7.35 (t, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 6.66 (br. d, 1H),6.36 (d, J = 1.88 Hz, 1H), 5.19 (s, 2H), 4.20 (s, 3H), 3.82 (s, 3H). 11

C₂₈H₂₁ClN₄O₅S 2.413/A 561.0994 561.0982 ¹H NMR (CDCl₃) δ ppm: 7.83 (br.s, 1H), 7.79-7.80 (m, 1H), 7.76 (s, 1H), 7.67 (br. d, J = 7.7 Hz, 2H),7.57 (s, 1H), 7.42-7.55 (m, 1H), 7.31-7.36 (m, 2H), 7.20 (s, 1H), 7.11(s, 1H), 6.59 (br. d, 1H), 6.30 (d, J = 1.84 Hz, 1H), 5.13 (s, 2H), 4.14(s, 3H), 3.75 (s, 3H). 12

C₂₈H₂₀Cl₂N₄O₅S 2.327/A 595.0604 595.0596 ¹H NMR (CDCl₃) δ ppm: 7.75 (s,1H), 7.72 (br. d, 1H), 7.57 (br. s, 1H), 7.41 (br. s, 1H), 7.34 (t, J =7.8 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 8.5Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 7.09 (s, 1H), 6.60 (br. d, 1H), 6.32(d, J = 1.86 Hz, 1H), 5.14 (s, 2H), 4.14 (s, 3H), 3.76 (s, 3H). 13

C₂₉H₂₁F₃N₄O₅S 2.313/A 595.1258 595.126 ¹H NMR (CDCl₃) δ ppm: 7.75 (s,1H), 7.68 (d, J = 7.8 Hz, 1H), 7.63 (br. d, J = 7.9 Hz, 1H), 7.49-7.62(m, 4H), 7.43 (br. s, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8Hz, 1H), 7.03 (s, 1H), 6.60 (br. d, 1H), 6.30 (d, J = 1.9 Hz, 1H), 5.12(s, 2H), 4.12 (s, 3H), 3.75 (s, 3H). 14

C₂₈H₁₉F₃N₄O₅S 2.373/A 581.1101 581.1103 ¹H NMR (CDCl₃) δ ppm: 8.18 (br.d, 1H), 7.8-7.87 (m, 1H), 7.76 (s, 1H), 7.63 (br. s, 1H), 7.60 (d, J =8.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.12(s, 1H), 7.03-7.09 (m, 1H), 6.60 (d, J = 1.8 Hz, 1H), 6.31 (d, J = 1.8Hz, 1H), 5.14 (s, 2H), 4.15 (s, 3H), 3.76 (s, 3H). 15

C₃₂H₂₄N₄O₅S 2.385/A 577.154 577.1535 ¹H NMR (CDCl₃) δ ppm: 9.06 (d, J =8.6 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H), 8.07(d, J = 7.7 Hz, 1H), 7.41-7.87 (m, 7H), 7.36 (t, J = 7.9 Hz, 1H), 7.22(d, J = 7.5 Hz, 1H), 7.12 (s, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.32 (d, J= 1.8 Hz, 1H), 5.16 (s, 2H), 4.15 (s, 3H), 3.76 (s, 3H). 16

C₂₉H₂₁N₅O₅S 2.351/A 552.1336 552.1327 ¹H NMR (CDCl₃) δ ppm: 8.21 (s,1H), 8.16 (br. s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.75-7.77 (m, 2H), 7.61 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 7.9Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.04 (s, 1H), 6.64 (br. d, 1H), 6.33(d, J = 1.8 Hz, 1H), 5.16 (s, 2H), 4.17 (s, 3H), 3.80 (s, 3H). 17

C₃₀H₂₆N₄O₆S 2.387/A 571.1646 571.1648 ¹H NMR (CDCl₃) δ ppm: 8.26 (br. s,1H), 7.75 (s, 1H), 7.49-7.52 (m, 2H), 7.25-7.36 (m, 6H), 7.16 (m,overlapping with CHCl₃, 1H), 7.00 (s, 1H), 6.61 (br. d, 1H), 6.29 (d, J= 1.8 Hz, 1H), 5.09 (s, 2H), 4.59 (s, 2H), 4.12 (s, 3H), 4.02 (s, 2H),3.75 (s, 3H). 18

C₂₉H₂₄N₄O₆S 2.337/A 557.1487 557.1514 ¹H NMR (CDCl₃) δ ppm: 7.72- 7.79(m, 4H), 7.66 (br. d, 1H), 7.57 (br. s, 1H), 7.32 (t, J = 7.9 Hz, 1H),7.15-7.16 (m, 1H), 7.11 (s, 1H), 6.89 (br. d, J = 8.8 Hz, 2H), 6.59 (br.d, 1H), 6.30 (d, J = 1.8 Hz, 1H), 5.13 (s, 2H), 4.14 (s, 3H), 3.79 (s,3H), 3.75 (s, 3H). 19

C₂₈H₂₀Cl₂N₄O₅S 2.540/A 595.0604 595.0627 ¹H NMR (CDCl₃) δ ppm: 7.81 (br.s, 1H), 7.75 (s, 1H), 7.67 (d, J = 1.9 Hz, 2H), 7.65 (br. d, 1H), 7.54(br. s, 1H), 7.44 (t, J = 1.9 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.19(br. d, overlapping with CHCl₃, 1H), 7.04 (s, 1H), 6.60 (br. d, 1H),6.29 (d, J = 1.9 Hz, 1H), 5.12 (s, 2H), 4.13 (s, 3H), 3.75 (s, 3H). 20

C₂₉H₂₄N₄O₅S 2.387/A 541.154 541.1566 ¹H NMR (CDCl₃) δ ppm: 7.77 (br. s,1H), 7.76 (s, 1H), 7.68 (br. d, J = 8 Hz, 1H), 7.62 (s, 1H), 7.57- 7.60(m, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.26-7.32 (m, 2H), 7.19 (m,overlapping with CHCl₃, 1H), 7.06 (s, 1H), 6.60 (br. d, 1H), 6.30 (d, J= 1.9 Hz, 1H), 5.13 (s, 2H), 4.13 (s, 3H), 3.75 (s, 3H), 2.35 (s, 3H).21

C₂₈H₁₉F₃N₄O₅S 2.320/A 581.1101 581.1129 ¹H NMR (CDCl₃) δ ppm: 7.77 (s,1H), 7.70 (br. d, J = 8 Hz, 1H), 7.64 (br. s, 1H), 7.56 (br. s, 1H),7.34 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 6.67-6.73 (m, 2H), 6.61 (br. d, 1H), 6.31 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H),4.15 (s, 3H), 3.77 (s, 3H). 22

C₂₉H₂₂N₄O₇S 2.338/A 571.1282 571.1308 ¹H NMR (CDCl₃) δ ppm: 7.76 (s,1H), 7.7 (br. s, 1H), 7.64 (br. d, J = 8 Hz, 1H), 7.55 (br. s, 1H),7.29- 7.34 (m, 3H), 7.15 (m, overlapping with CHCl₃, 1H), 7.09 (s, 1H),6.79 (d, J = 8.05 Hz, 1H), 6.59 (br. d, 1H), 6.30 (d, J = 1.77 Hz, 1H),5.97 (s, 2H), 5.12 (s, 2H), 4.14 (s, 3H), 3.75 (s, 3H). 23

C₃₂H₂₄N₄O₅S 2.428/A 577.154 577.1565 ¹H NMR (CDCl₃) δ ppm: 8.32 (s, 1H),7.96 (br. s, 1H), 7.87-7.90 (m, 3H), 7.81-7.83 (m, 1H), 7.72- 7.75 (m,2H), 7.63 (br. s, 1H), 7.46-7.53 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.20(d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 6.60 (br. d, 1H), 6.31 (d, J = 1.86Hz, 1H), 5.14 (s, 2H), 4.12 (s, 3H), 3.75 (s, 3H). 24

C₂₈H₂₁IN₄O₅S 2.327/A 653.035 653.037 ¹H NMR (CDCl₃) δ ppm: 7.83 (d, J =7.9 Hz, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.47(br. d, J = 7.6 Hz, 1H), 7.42 (br. s, 1H), 7.37 (d, J = 8.0 Hz, 1H),7.33 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.07 (br. t, 1H),6.91 (s, 1H), 6.60 (br. d, 1H), 6.31 (d, J = 1.4 Hz, 1H), 5.13 (s, 2H),4.12 (s, 3H), 3.75 (s, 3H). 25

C₂₈H₂₁ClN₄O₅S 2.317/A 561.0993 561.0994 ¹H NMR (CDCl₃) δ ppm: 7.80 (br.s, 1H), 7.75 (s, 1H), 7.68 (dd, J = 7.3, 1.9 Hz, 1H), 7.64 (br. d, J =8.1 Hz, 1H), 7.60 (br. s, 1H), 7.28- 7.40 (m, 4H), 7.21 (d, J = 7.8 Hz,1H), 7.03 (s, 1H), 6.60 (br. d, 1H), 6.31 (d, J = 1.8 Hz, 1H), 5.13 (s,2H), 4.12 (s, 3H), 3.75 (s, 3H). 26

C₂₈H₂₁FN₄O₅S 2.328/A 545.1289 545.1283 ¹H NMR (CDCl₃) δ ppm: 8.42 (br.d, J = 15.8 Hz, 1H), 8.09 (dt, J = 8.0, 1.8 Hz, 1H), 7.76 (br. s, 1H),7.67 (s, 1H), 7.61 (d, J = 8.15 Hz, 1H), 7.41-7.47 (m, 1H), 7.33 (t, J =7.8 Hz, 1H), 7.21-7.25 (m, 2H), 7.12 (s, 1H), 7.11 (dd, J = 12.4, 8.1Hz, 1H), 6.59 (br. d, 1H), 6.31 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.15(s, 3H), 3.75 (s, 3H). 27

C₂₉H₂₄N₄O₅S 2.339/A 541.154 541.1538 ¹H NMR (CDCl₃) δ ppm: 7.77 (s, 1H),7.64 (br. d, J = 7.8 Hz, 1H), 7.56 (br. s, 1H), 7.41-7.44 (m, 2H), 7.32(t, J = 7.8 Hz, 1H), 7.23-7.30 (m, 1H), 7.19-7.20 (m, 3H), 7.02 (s, 1H),6.60 (br. d, 1H), 6.30 (d, J = 1.8 Hz, 1H), 5.12 (s, 2H), 4.12 (s, 3H),3.75 (s, 3H), 2.44 (s, 3H). 28

C₂₈H₂₁FN₄O₅S 2.358/A 545.1289 545.1176 ¹H NMR (CDCl₃) δ ppm: 7.82 (br.s, 1H), 7.76 (s, 1H), 7.68 (br. d, J = 8.0 Hz, 1H), 7.51-7.57 (m, 3H),7.37-7.41 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.13-7.20 (m, 3H), 6.59(br. d, 1H), 6.30 (d, J = 1.8 Hz, 1H), 5.13 (s, 2H), 4.15 (s, 3H), 3.75(s, 3H). 29

C₂₉H₂₄F₃N₄O₆S 2.356/A 557.1489 557.1357 ¹H NMR (CDCl₃) δ ppm: 9.75 (br.s, 1H), 8.21 (dd, J = 7.8, 1.8 Hz, 1H), 7.76 (s, 1H), 7.65 (br. s, 1H),7.62 (br. d, J = 7.9 Hz, 1H), 7.4- 7.44 (m, 1H), 7.31 (t, J = 7.8 Hz,1H), 7.20 (m, 1H), 7.07 (br. d, J = 8 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J= 8.3 Hz, 1H), 6.61 (br. d, 1H), 6.32 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H),4.12 (s, 3H), 3.98 (s, 3H), 3.75 (s, 3H). 30

C₂₉H₂₀F₄N₄O₅S 2.424/A 613.1163 613.1188 ¹H NMR (CDCl₃) δ ppm: 8.09 (br.dd, J = 6.8, 2.0 Hz, 1H), 8.01-8.04 (m, 1H), 7.86 (br. s, 1H), 7.76 (s,1H), 7.70 (br. d, J = 8 Hz, 1H), 7.55 (br. s, 1H), 7.34 (t, J = 7.8 Hz,1H), 7.25 (t, J = 9.2 Hz, 1H), 7.20 (m, 1H), 7.07 (s, 1H), 6.60 (br. d,1H), 6.30 (d, J = 1.6 Hz, 1H), 5.13 (s, 2H), 4.13 (s, 3H), 3.75 (s, 3H).31

C₃₁H₂₈N₄O₅S 2.468/A 569.1853 569.1851 ¹H NMR (CDCl₃) δ ppm: 7.86 (s,2H), 7.82 (d, J = 8.2 Hz, 2H), 7.76 (br. d, J = 8 Hz, 1H), 7.67 (br. s,1H), 7.42 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.25 (m,overlapping with CHCl3, 1H), 7.17 (s, 1H), 6.70 (br. d, 1H), 6.40 (d, J= 2.0 Hz, 1H), 5.22 (s, 2H), 4.23 (s, 3H), 3.85 (s, 3H), 2.67 (t, J =7.6 Hz, 2H), 1.72-1.75 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). 32

C₂₉H₂₄N₄O₅S 2.376/A 541.154 541.1565 ¹H NMR (CDCl₃) δ ppm: 7.77 (br. s,1H), 7.76 (s, 1H), 7.70 (br. d, J = 8.0 Hz, 2H), 7.67 (br. dd, J = 7.9,1.5 Hz, 1H), 7.58 (br. s, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.20 (br. d, J= 8.0 Hz, 2H), 7.17 (m, overlapping with CHCl3, 1H), 7.10 (s, 1H), 6.60(br. d, 1H), 6.30 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H), 4.14 (s, 3H), 3.75(s, 3H), 2.34 (s, 3H). 33

C₂₈H₂₁N₅O₇S 2.358/A 572.1234 572.1255 ¹H NMR (CDCl₃) δ ppm: 8.25 (d, J =8.8 Hz, 2H), 7.99 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 7.75(br. d, J = 7.6 Hz, 1H), 7.55 (br. s, 1H), 7.35 (t, J = 7.9 Hz, 1H),7.19 (m, overlapping with CHCl3, 1H), 7.10 (s, 1H), 6.60 (br. d, 1H),6.30 (d, J = 1.8 Hz, 1H), 5.13 (s, 2H), 4.14 (s, 3H), 3.75 (s, 3H). 34

C₃₀H₂₄N₄O₇S 2.367/A 585.1438 585.1454 ¹H NMR (CDCl₃) δ ppm: 8.07 (d, J =8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.86 (s, 1H), 7.76 (s, 1H), 7.71(br. dd, J = 7.6, 1.1 Hz, 1H), 7.58 (br. s, 1H), 7.34 (t, J = 7.9 Hz,1H), 7.19 (m, overlapping with CHCl3, 1H), 7.09 (s, 1H), 6.60 (br. d,1H), 6.30 (d, J = 1.86 Hz, 1H), 5.13 (s, 2H), 4.14 (s, 3H), 3.87 (s,3H), 3.75 (s, 3H). 35

C₂₉H₂₄N₄O₆S 2.372/A 557.1489 557.1511 ¹H NMR (CDCl₃) δ ppm: 8.23 (br. s,1H), 7.75 (s, 1H), 7.57 (br. s, 1H), 7.54 (br. d, J = 8 Hz, 1H),7.25-7.32 (m, 3H), 7.20 (d, J = 7.7 Hz, 1H), 7.01 (s, 1H), 6.97 (t, J =7.4 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.61 (br. d, 1H), 6.29 (d, J =1.6 Hz, 1H), 5.10 (s, 2H), 4.55 (s, 2H), 4.12 (s, 3H), 3.75 (s, 3H). 36

C₂₉H₂₁N₅O₅S 2.315/A 552.1336 552.1254 ¹H NMR (CDCl₃) δ ppm: 7.97 (br. d,J = 8.6 Hz, 2H), 7.90 (br. s, 1H), 7.82 (s, 1H), 7.75-7.80 (m, 3H), 7.59(br. s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.24 (m, overlapping with CHCl3,1H), 7.08 (d, J = 0.7 Hz, 1H), 6.67 (br. d, 1H), 6.35 (d, J = 1.9 Hz,1H), 5.19 (s, 2H), 4.19 (s, 3H), 3.81 (s, 3H). 37

C₃₂H₃₀N₄O₅S 2.405/A 583.201 583.2019 ¹H NMR (CDCl₃) δ ppm: 7.78 (br. s,1H), 7.74 (d, J = 8.4 Hz, 2H), 7.67 (br. d, J = 8.3 Hz, 1H), 7.59 (br.s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.2 (m,overlapping with CHCl3, 2H), 7.1 (br. s, 1H), 6.61 (br. s, 1H), 6.31 (s,1H), 5.13 (s, 2H), 4.13 (s, 3H), 3.75 (s, 3H), 1.27 (s, 9H). 38

C₂₉H₂₅N₅O₅S 2.346/A 556.1649 556.1556 ¹H NMR (DMSO-d₆) δ ppm: 8.60 (s,1H), 8.34 (s, 1H), 7.50 (t, J = 1.7 Hz, 1H), 7.34-7.36 (br. d, 1H),7.19-7.32 (m, 7H), 6.99 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 0.7 Hz, 1H),6.78 (br. d, 1H), 6.56 (t, J = 5.8 Hz, 1H), 6.46 (d, J = 1.9 Hz, 1H),5.15 (s, 2H), 4.25 (d, J = 5.8 Hz, 1H), 4.16 (s, 3H), 3.75 (s, 3H). 39

C₂₈H₂₁IN₄O₅S 2.444/A 653.035 653.0362 ¹H NMR (CDCl₃) δ ppm: 7.82 (d, J =8.2 Hz, 2H), 7.75-7.8 (m, 2H), 7.74 (br. d, J = 8.6 Hz, 1H), 7.60 (s,1H), 7.59 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.2-7.3 (m,1H), 7.09 (br. s, 1H), 6.66 (br. d, 1H), 6.35 (d, J = 1.5 Hz, 1H), 5.17(s, 2H), 4.18 (s, 3H), 3.81 (s, 3H). 40

C₃₁H₂₈N₄O₆S 2.453/A 585.1802 585.1812 ¹H NMR (CDCl₃) δ ppm: 8.62 (br. s,1H), 7.81 (s, 1H), 7.64 (br. s, 1H), 7.59 (br. d, J = 8 Hz, 1H), 7.35(t, J = 7.9 Hz, 1H), 7.25-7.3 (m, 3H), 7.07-7.11 (m, 1H), 7.06 (d, J =0.53 Hz, 1H), 6.97-7.0 (m, 2H), 6.67 (br. d, 1H), 6.35 (d, J = 1.9 Hz,1H), 5.15 (s, 2H), 4.18 (s, 3H), 3.81 (s, 3H), 1.57 (s, 6H). 41

C₂₉H₂₁F₃N₄O₆S 2.311/A 611.1207 611.1238 ¹H NMR (CDCl₃) δ ppm: 7.93 (d, J= 8.4 Hz, 2H), 7.86 (br. s, 1H), 7.82 (br. s, 1H), 7.76 (d, J = 8.1 Hz,1H), 7.61 (br. s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 8.4 Hz,2H), 7.24 (d, J = 7.2 Hz, 1H), 7.1 (br. s, 1H), 6.67 (br. s, 1H), 6.36(br. s, 1H), 5.18 (s, 2H), 4.18 (s, 3H), 3.81 (s, 3H). 42

C₃₀H₂₆N₄O₇S 2.392/A 587.1595 587.1626 ¹H NMR (CDCl₃) δ ppm: 9.72 (s,1H), 8.22 (d, J = 8.4 Hz, 1H), 7.8 (br. s, 1H), 7.70 (s, 1H) 7.64 (dd, J= 8.6. 1.0 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.1-7.25 (m, 2H), 6.66(br. s, 1H), 6.62 (dd, J = 8.6. 2.0 Hz, 1H), 6.5 (br. d, 1H), 6.37 (br.d, 1H), 5.19 (s, 2H), 4.19 (s, 3H), 4.0 (s, 3H), 3.85 (s, 3H), 3.81 (s,3H). 43

C₃₀H₂₇N₅O₅S 2.351/A 570.1806 570.1837 ¹H NMR (CDCl₃) δ ppm: 7.83 (br. s,1H), 7.80 (br. s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.70 (br. d, J = 9 Hz,1H), 7.65 (br. s, 1H), 7.37 (t, J = 8.6 Hz, 1H), 7.21 (d, J = 7.8 Hz,1H), 7.19 (br. s, 1H), 6.74 (d, J = 8.9 Hz, 2H), 6.65 (br. d, 1H), 6.37(d, J = 1.6 Hz, 1H), 5.19 (s, 2H), 4.21 (s, 3H), 3.81 (s, 3H), 3.02 (s,6H). 44

C₂₅H₁₉N₅O₆S 2.269/A 518.1129 518.1079 ¹H NMR (CDCl₃) δ ppm: 8.3 (d, J =1.8 Hz, 1H), 8.2 (br. s, 1H), 7.76 (s, 1H), 7.65 (br. s, 1H), 7.61 (br.d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 8.15 Hz, 1H),7.08 (s, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.61 (br. d, 1H), 6.30 (d, J =1.9 Hz, 1H), 5.14 (s, 2H), 4.14 (s, 3H), 3.75 (s, 3H). 45

C₂₇H₂₃N₅O₆S 2.281/A 546.1442 546.1399 ¹H NMR (CDCl₃) δ ppm: 7.8 (br. s,1H), 7.51-7.55 (m, 2H), 7.32 (t, J = 8.2 Hz, 1H), 7.26 (br. s, 1H), 7.20(d, J = 8.2 Hz, 1H), 7.11 (br. s, 1H), 6.60 (br. d, 1H), 6.30 (d, J =1.6 Hz, 1H), 5.12 (s, 2H), 4.15 (s, 3H), 3.76 (s, 3H), 2.59 (s, 3H),2.42 (s, 3H). 46

C₂₈H₂₃N₅O₆S 2.370/A 558.1442 558.1408 ¹H NMR (CDCl₃) δ ppm: 8.70 (d, J =2.5 Hz, 1H), 8.06 (dd, J = 8.7, 2.5 Hz, 1H), 7.86 (br. s, 1H), 7.81 (s,1H), 7.70 (dd, J = 8.1, 1.2 Hz, 1H), 7.61 (br. s, 1H), 7.38 (t, J = 7.9Hz, 1H), 7.22-7.24 (m, 1H), 7.07 (s, 1H), 6.79 (dd, J = 8.7, 0.65 Hz,1H), 6.66 (br. d, 1H), 6.35 (d, J = 1.9 Hz, 1H), 5.17 (s, 2H), 4.18 (s,3H), 3.98 (s, 3H), 3.81 (s, 3H). 47

C₂₇H₂₃N₅O₆S 2.255/A 546.1442 546.1469 ¹H NMR (CDCl₃) δ ppm: 7.77 (s,1H), 7.47-7.53 (m, 2H), 7.46 (br. s, 1H), 7.27 (t, J = 7.8 Hz, 1H),7.14-7.17 (m, 1H), 7.12 (s, 1H), 6.59 (br. d, 1H), 6.29 (d, J = 1.9 Hz,1H), 6.08 (s, 1H), 5.09 (s, 2H), 4.15 (s, 3H), 3.79 (s, 2H), 3.75 (s,3H), 2.22 (s, 3H). 48

C₂₇H₂₀FN₅O₅S 2.218/A 546.1242 546.1266 ¹H NMR (CDCl₃) δ ppm: 8.32 (d,5.1 Hz, 1H), 7.93 (br. s, 1H), 7.76 (s, 1H), 7.73 (br. d, 1H), 7.52-7.56 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.32 (br. s, 1H), 7.20 (d, J =8.5 Hz, 1H), 7.10 (s, 1H), 6.60 (br. d, 1H), 6.30 (d, J = 1.9 Hz, 1H),5.13 (s, 2H), 4.14 (s, 3H), 3.75 (s, 3H). 49

C₂₈H₂₅N₅O₅S₂ 2.281/A 576.137 576.1411 ¹H NMR (CDCl₃) δ ppm: 9.87 (s,1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.49 (d, J = 6.5 Hz, 1H), 7.31 (t, J =7.8 Hz, 1H), 7.20-7.23 (m, 1H), 7.11 (s, 1H), 6.64 (br. d, 1H), 6.34 (d,J = 1.9 Hz, 1H), 5.13 (s, 2H), 4.20 (s, 3H), 3.88 (s, 2H), 3.80 (s, 3H),2.82 (s, 3H), 2.57 (s, 3H). 50

C₂₇H₂₃N₅O₅S₂ 2.315/A 562.1213 562.1242 ¹H NMR (CDCl₃) δ ppm: 7.82 (s,1H), 7.60 (br. d, J = 8.3 Hz, 1H), 7.58 (br. s, 1H), 7.45 (br. s, 1H),7.38 (t, J = 7.8 Hz, 1H), 7.25- 7.27 (m, 1H), 7.16 (s, 1H), 6.66 (br. d,1H), 6.35 (d, J = 1.9 Hz, 1H), 5.18 (s, 2H), 4.21 (s, 3H), 3.81 (s, 3H),2.70 (s, 3H), 2.65 (br. s, 3H). 51

C₃₃H₂₅N₅O₆S 2.416/A 620.1598 620.1612 ¹H NMR (CDCl₃) δ ppm: 8.61 (d, J =2.5 Hz, 1H), 8.14 (dd, J = 8.6, 2.5 Hz, 1H), 7.80 (br. s, 1H), 7.76 (s,1H), 7.65 (br. d, J = 8 Hz, 1H), 7.57 (br. s, 1H), 7.31-7.38 (m, 3H),7.15-7.20 (m, 2H), 7.06- 7.13 (m, 3H), 6.91 (d, J = 8.7 Hz, 1H), 6.59(br. d, 1H), 6.30 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H), 4.15 (s, 3H), 3.75(s, 3H). 52

C₂₇H₂₀N₄O₄S 2.361/A 497.1278 497.1291 ¹H NMR (CDCl₃) δ ppm: 7.80- 7.82(m, 4H), 7.66 (br. d, J = 8 Hz, 1H), 7.60 (br. s, 1H), 7.39-7.47 (m,3H), 7.32 (t, J = 7.9 Hz, 1H), 7.18 (d, J = 8 Hz, 1H), 7.12 (s, 1H),7.05-7.12 (m, 2H), 6.63 (dd, J = 7.0, 1.7 Hz, 1H), 5.16 (s, 2H), 4.12(s, 3H). 53

C₂₇H₂₀ClN₅O₅S 2.343/A 562.0946 562.0956 ¹H NMR (DMSO-d₆) δ ppm: 10.49(s, 1H), 8.88 (d, J = 2.5 Hz, 1H), 8.32 (s, 1H), 8.28 (dd, J = 8.3, 2.5Hz, 1H), 7.85 (br. s, 1H), 7.69 (dd, J = 8.3, 1.1 Hz, 1H), 7.64 (d, J =8.3 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.93(s, 1H), 6.77 (br. d, 1H), 6.46 (d, J = 1.8 Hz, 1H), 5.20 (s, 2H), 4.13(s, 3H), 3.72 (s, 3H). 54

C₃₀H₂₁F₆N₅O₆S 2.395/A 694.1189 694.1209 ¹H NMR (CDCl₃) δ ppm: 8.51 (s,1H), 7.82 (s, 1H), 7.75 (br. dd, 1H), 7.66 (br. s, 1H), 7.59 (br. s,1H), 7.40 (t, J = 7.9 Hz, 1H), 7.24- 7.27 (m, 1H), 7.21 (s, 1H), 7.16(s, 1H), 6.66 (br. d, 1H), 6.37 (d, J = 1.6 Hz, 1H), 5.19 (s, 2H), 4.83(q, J = 8.2 Hz, 2H), 4.20 (s, 3H), 3.82 (s, 3H). 55

C₂₇H₁₉Cl₂N₅O₅S 2.453/A 596.0557 596.0567 ¹H NMR (CDCl₃) δ ppm: 8.31 (br.s, 1H), 7.73-7.76 (m, 2H), 7.60 (s, 2H), 7.52 (br. s, 1H), 7.33 (t, J =7.8 Hz, 1H), 7.15-7.18 (m, 1H), 7.1 (s, 1H), 6.56 (br. d, 1H), 6.26 (d,J = 1.7 Hz, 1H), 5.11 (s, 2H), 4.14 (s, 3H), 3.74 (s, 3H). 56

C₂₇H₂₁N₅O₆S 2.215/A 544.1285 544.1297 ¹H NMR (CDCl₃) δ ppm: 8.69 (br. s,1H), 7.71-7.76 (m, 2H), 7.59 (br. s, 1H), 7.27-7.33 (m, 2H), 7.14 (d, J= 7.5 Hz, 1H), 7.07 (s, 1H), 7.0 (br. s, 1H), 6.72 (br. d, J = 7 Hz,1H), 6.56 (br. s, 1H), 6.26 (br. s, 1H), 5.10 (s, 2H), 4.11 (s, 3H),3.73 (s, 3H). 57

C₂₆H₂₀N₆O₅S 2.273/A 529.1289 529.1306 ¹H NMR (CDCl₃) δ ppm: 9.0-9.6 (br.s, 5H), 8.26 (br. s, 1H), 7.78 (br. d, J = 8 Hz, 1H), 7.58 (br. s, 1H),7.35 (t, J = 7.8 Hz, 1H), 7.18- 7.19 (m, 1H), 6.59 (br. s, 1H), 6.30 (s,1H), 5.14 (s, 2H), 4.15 (s, 3H), 3.75 (s, 3H). 58

C₂₇H₂₀ClN₅O₅S 2.261/A 562.0946 562.0948 ¹H NMR (CDCl₃) δ ppm: 8.45 (dd,J = 4.8, 1.9 Hz, 1H), 8.12 (dd, J = 7.6, 1.9 Hz, 1H), 8.07 (br. s, 1H),7.75 (s, 1H), 7.64 (br. d, J = 8 Hz, 1H), 7.61 (br. s, 1H), 7.31-7.37(m, 2H), 7.23 (br. d, J = 7.8 Hz, 1H), 7.03 (s, 1H), 6.61 (br. d, 1H),6.31 (d, J = 1.8 Hz, 1H), 5.13 (s, 2H), 4.12 (s, 3H), 3.75 (s, 3H). 59

C₃₂H₂₅N₅O₆S 2.371/A 608.1598 608.1604 ¹H NMR (CDCl₃) δ ppm: 7.83 (s,1H), 7.73-7.76 (m, 2H), 7.41- 7.53 (m, 4H), 7.39 (br. s, 1H), 7.33 (t, J= 7.8 Hz, 1H), 7.31 (br. s, 1H), 7.22-7.24 (m, 1H), 7.09 (s, 1H), 6.66(br. d, 1H), 6.32 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.20 (s, 3H), 3.81(s, 3H), 2.53 (s, 3H). 60

C₃₁H₂₃N₅O₆S 2.377/A 594.1442 594.1445 ¹H NMR (CDCl₃) δ ppm: 8.60 (s,1H), 7.77-7.81 (m, 2H), 7.76 (s, 1H), 7.42-7.51 (m, 5H), 7.35 (br. s,1H), 7.28 (t, J = 7.9 Hz, 1H), 7.15-7.18 (m, 1H), 7.09 (s, 1H), 6.59(br. d, 1H), 6.26 (d, J = 1.8 Hz, 1H), 5.09 (s, 2H), 4.15 (s, 3H), 3.75(s, 3H). 61

C₂₇H₂₀FN₅O₅S 2.271/A 546.1242 546.1248 ¹H NMR (CDCl₃) δ ppm: 8.55- 8.60(m, 1H), 8.49 (br. d, J = 14 Hz, 1H), 8.29-8.31 (m, 1H), 7.76 (s, 1H),7.68 (s, 1H), 7.60 (br. d, J = 7.8 Hz, 1H), 7.32-7.37 (m, 2H), 7.25 (d,J = 7.5 Hz, 1H), 7.12 (s, 1H), 6.60 (br. d, 1H), 6.31 (d, J = 1.8 Hz,1H), 5.14 (s, 2H), 4.15 (s, 3H), 3.75 (s, 3H). 62

C₃₆H₂₇F₃N₄O₆S 2.599/A 701.1676 701.1524 ¹H NMR (CDCl₃) δ ppm: 7.88 (br.s, 1H), 7.75 (br. s, 1H), 7.64 (br. d, J = 8.2 Hz, 1H), 7.58-7.62 (m,3H), 7.25-7.44 (m, 7H), 7.20 (d, J = 7.3 Hz, 1H), 7.03 (br. s, 1H), 6.60(br. s, 1H), 6.30 (br. s, 1H), 5.12 (s, 2H), 5.06 (s, 2H), 4.12 (s, 3H),3.74 (s, 3H). 63

C₂₉H₂₃ClN₄O₆S 2.456/A 591.11 591.0974 ¹H NMR (CDCl₃) δ ppm: 7.85 (br. s,1H), 7.82 (br. s, 1H), 7.73 (br. d, J = 8 Hz, 1H), 7.67 (s, 1H), 7.43(t, J = 8 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.6 Hz, 1H),7.15 (br. s, 1H), 7.08 (s, 1H), 6.70 (br. s, 1H), 6.39 (br. s, 1H), 5.22(s, 2H), 4.22 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H). 64

C₂₈H₂₂ClN₅O₅S 2.282/A 576.1103 576.1098 ¹H NMR (DMSO-d₆) δ ppm: 10.57(s, 1H), 8.31 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.80 (br. s, 1H), 7.62(br. d, J = 8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.8 Hz,1H), 7.18 (br. d, J = 8 Hz, 1H), 6.92 (s, 1H), 6.76 (br. d, 1H), 6.46(d, J = 1.9 Hz, 1H), 5.19 (s, 2H), 4.13 (s, 3H), 3.73 (s, 3H), 2.42 (s,3H). 65

C₂₇H₂₀BrN₅O₅S 2.449/A 606.0441 606.0305 ¹H NMR (CDCl₃) δ ppm: 9.86 (br.s, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.02 (dd, J= 8.4, 2.3 Hz, 1H), 7.79-7.82 (m, 3H), 7.40 (t, J = 7.8 Hz, 1H), 7.26(d, J = 7.5 Hz, 1H), 7.11 (s, 1H), 6.67 (br. d, 1H), 6.37 (d, J = 1.9Hz, 1H), 5.20 (s, 2H), 4.19 (s, 3H), 3.82 (s, 3H). 66

C₃₃H₂₆N₆O₅S 2.467/A 619.1758 619.1575 ¹H NMR (CDCl₃) δ ppm: 8.77 (s,1H), 8.34-8.37 (m, 2H), 7.99 (br. s, 1H), 7.75 (br. d, J = 8 Hz, 1H),7.73 (s, 1H), 7.56 (br. s, 1H), 7.38- 7.43 (m, 3H), 7.34 (t, J = 7.9 Hz,1H), 7.17-7.19 (m, 1H), 7.14 (s, 1H), 6.53 (br. d, 1H), 6.30 (d, J = 1.9Hz, 1H), 5.14 (s, 2H), 4.13 (s, 3H), 3.72 (s, 3H), 2.65 (s, 3H). 67

C₃₅H₂₇ClN₄O₆S 2.527/A 667.1413 667.1447 ¹H NMR (CDCl₃) δ ppm: 7.82 (s,1H), 7.76 (br. s, 1H), 7.69 (br. d, J = 8 Hz, 1H), 7.63 (br. s, 1H),7.31-7.42 (m, 8H), 7.24-7.26 (m, 1H), 7.12 (t, J = 2 Hz, 1H), 7.09 (s,1H), 6.67 (br. d, 1H), 6.36 (d, J = 1.9 Hz, 1H), 5.18 (s, 2H), 5.09 (s,2H), 4.18 (s, 3H), 3.81 (s, 3H). 68

C₂₈H₂₁F₂N₇O₅S₂ 2.432/A 638.1086 638.112 ¹H NMR (CDCl₃) δ ppm: 9.04 (s,1H), 8.45 (s, 1H), 7.86 (br. s, 1H), 7.75-7.82 (m, 2H), 7.42 (t, J = 8.0Hz, 1H), 7.27-7.29 (m, 1H), 7.16 (s, 1H), 6.70 (br. d, 1H), 6.40 (d, J =1.6 Hz, 1H), 5.23 (s, 2H), 4.23 (s, 3H), 3.85 (s, 3H), 2.22 (t, J = 18.4Hz, 3H). 69

C₂₆H₂₀N₆O₅S 2.243/A 529.1289 529.1325 ¹H NMR (CDCl₃) δ ppm: 9.62 (s,1H), 9.31 (d, J = 5.2 Hz, 1H), 8.63 (br. s, 1H), 7.88-7.90 (m, 1H), 7.81(br. d, J = 8 Hz, 1H), 7.79 (s, 1H), 7.58 (br. s, 1H), 7.34 (t, J = 7.9Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.0 (s, 1H), 6.63 (br. d, 1H), 6.31(d, J = 1.7 Hz, 1H), 5.18 (s, 2H), 4.17 (s, 3H), 3.80 (s, 3H). 70

C₂₆H₁₈F₃N₅O₅S₂ 2.180/A 602.0774 602.0797 ¹H NMR (CDCl₃) δ ppm: 9.01 (br.s, 1H), 8.38 (s, 1H), 7.76 (s, 1H), 7.73 (br. s, 1H), 7.65 (br. dd, J =8, 1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.08(s, 1H), 6.61 (br. d, 1H), 6.31 (d, J = 1.9 Hz, 1H), 5.14 (s, 2H), 4.14(s, 3H), 3.76 (s, 3H). 71

C₃₀H₂₃F₃N₄O₅S 2.437/A 609.1414 609.1424 ¹H NMR (CDCl₃) δ ppm: 7.89 (br.s, 1H), 7.84 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.69 (br. d, J = 8.5Hz, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.17-7.21 (m, 1H), 7.13 (s, 1H), 6.59 (br. d, 1H), 6.31 (d, J = 1.9 Hz, 1H),5.14 (s, 2H), 4.15 (s, 3H), 3.76 (s, 3H), 2.41 (s, 3H). 72

C₃₁H₂₃N₅O₅S₂ 2.494/A 610.1213 610.1229 ¹H NMR (CDCl₃) δ ppm: 9.26 (br.s, 1H), 8.12 (s, 1H), 7.90-7.95 (m, 2H), 7.76 (s, 1H), 7.70-7.73 (m,2H), 7.39-7.44 (m, 3H), 7.34 (t, J = 7.8 Hz, 1H), 7.22 (br. d, J = 8 Hz,1H), 7.03 (s, 1H), 6.62 (br. d, 1H), 6.32 (d, J = 1.9 Hz, 1H), 5.14 (s,2H), 4.12 (s, 3H), 3.76 (s, 3H). 73

C₂₈H₂₃N₅O₆S 2.412/A 558.1442 558.144 ¹H NMR (DMSO-d₆) δ ppm: 12.64 (s,1H), 12.14 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.78 (s,1H), 7.59 (br. dd, J = 8, 1 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.16 (d,J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.76 (br. d, 1H), 6.47 (d, J = 2.0 Hz,1H), 6.35 (d, J = 7.4 Hz, 1H), 5.19 (s, 2H), 4.13 (s, 3H), 3.73 (s, 3H),2.27 (s, 3H). 74

C₃₀H₂₁F₅N₄O₅S 2.061/A 661.1175 661.1154 ¹H NMR (CDCl₃) δ ppm: 8.06 (br.s, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.69 (br. d, J = 7.8Hz, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.34 (t, J = 8 Hz, 1H), 7.20 (d, J= 8.1 Hz, 1H), 7.05 (s, 1H), 6.60 (br. d, 1H), 6.56 (t, J = 72 Hz, 1H),6.30 (d, J = 1.5 Hz, 1H), 5.12 (s, 2H), 4.13 (s, 3H), 3.75 (s, 3H). 75

C₂₉H₂₃FN₄O₅S 2.018/A 559.1446 559.1467 ¹H NMR (CDCl₃) δ ppm: 7.82 (s,1H), 7.70 (br. d, J = 7.6 Hz, 1H), 7.62 (br. s, 1H), 7.49 (br. s, 1H),7.39 (t, J = 7.8 Hz, 1H), 7.2-7.3 (m, 3H), 7.08 (s, 1H), 7.05 (dt, J =8.3, 2.7 Hz, 1H), 6.67 (br. s, 1H), 6.37 (br. s, 1H), 5.18 (s, 2H), 4.18(s, 3H), 3.82 (s, 3H), 2.45 (s, 3H). 76

C₂₉H₂₀F₄N₄O₆S 2.152/A 629.1112 629.1133 ¹H NMR (CDCl₃) δ ppm: 7.82 (br.s, 2H), 7.72 (br. d, J = 7.8 Hz, 1H), 7.62 (br. s, 1H), 7.53 (br. s,2H), 7.40 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.13 (br. d, J= 8.6 Hz, 1H), 7.08 (s, 1H), 6.67 (br. s, 1H), 6.36 (br. s, 1H), 5.19(s, 2H), 4.19 (s, 3H), 3.82 (s, 3H). 77

C₃₁H₂₂FN₅O₅S₂ 2.793/B 628.1119 628.113 ¹H NMR (CDCl₃) δ ppm: 9.23 (s,1H), 8.13 (s, 1H), 7.91-7.95 (m, 2H), 7.77 (s, 1H), 7.74 (br. d, J = 8.2Hz, 1H), 7.71 (br. s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.9Hz, 1H), 7.11 (t, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.63 (br. d, 1H), 6.33(d, J = 1.8 Hz, 1H), 5.15 (s, 2H), 4.13 (s, 3H), 3.77 (s, 3H). 78

C₃₀H₂₄F₂N₄O₇S 2.648/B 623.1407 623.1436 ¹H NMR (CDCl₃) δ ppm: 7.85 (s,1H), 7.83 (br. s, 1H), 7.72 (br. d, J = 8.2 Hz, 1H), 7.67 (br. s, 1H),7.42 (t, J = 7.8 Hz, 1H), 7.25-7.3 (m, 2H), 7.19 (br. s, 1H), 7.11 (s,1H), 6.85 (t, J = 2.2 Hz, 1H), 6.70 (d, J = 2 Hz, 1H), 6.58 (t, J = 73Hz, 1H), 6.39 (d, J = 2 Hz, 1H), 5.21 (s, 2H), 4.21 (s, 3H), 3.88 (s,3H), 3.85 (s, 3H). 79

C₃₁H₂₂ClN₅O₅S₂ 3.048/B 644.0824 644.0847 ¹H NMR (CDCl₃) δ ppm: 9.26 (br.s, 1H), 8.28 (s, 1H), 8.18 (dd, J = 7.4, 2.4 Hz, 1H), 7.76 (s, 1H), 7.7-7.73 (m, 2H), 7.47 (dd, J = 7.5, 1.5 Hz, 1H), 7.31-7.39 (m, 3H), 7.22(d, J = 7.3 Hz, 1H), 7.03 (s, 1H), 6.62 (br. d, 1H), 6.32 (d, J = 2.0Hz, 1H), 5.14 (s, 2H), 4.12 (s, 3H), 3.76 (s, 3H). 80

C₃₂H₂₂F₃N₅O₅S₂ 2.562/A 678.1087 678.1111 ¹H NMR (CDCl₃) δ ppm: 9.21 (br.s, 1H), 8.21 (s, 1H), 8.18 (br. s, 1H), 8.12 (br. d, J = 7.9 Hz, 1H),7.77 (br. s, 2H), 7.71 (br. d, J = 7.5 Hz, 1H), 7.67 (br. d, J = 8.2 Hz,1H), 7.57 (t, J = 8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.4Hz, 1H), 7.04 (s, 1H), 6.63 (br. d, 1H), 6.34 (d, J = 2.0 Hz, 1H), 5.16(s, 2H), 4.13 (s, 3H), 3.77 (s, 3H).

Example 81 tert-Butyl(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)(methyl)carbamate

3-Formamidobenzyl formate

A solution of 3-aminobenzyl alcohol (2.00 g, 16.24 mmol) in formic acid(30 mL) was heated under reflux (bath temperature 110° C.) for 2 hours.The excess formic acid was evaporated under reduced pressure and theresidual oil was chromatographed on silica gel (elution toluene-ethylacetate 7:3) to give 2.47 g (85% yield) of the title material as a clearoil. HPLC (Method A): 1.255 min. ¹H NMR (CDCl₃, 400 MHz) δ ppm: (mixtureof rotamers) 8.72 and 8.69 (two s, 0.4H), 8.38 (two s, 0.5H), 8.13 and8.14 (two s, 0.9H), 8.0 (broad s, 0.4H), 7.61 (br. s, 0.5H), 7.49 (br.d, 0.6H), 7.32-7.38 (m, 1.5H), 7.19 (d, J=7.7 Hz, 0.5H), 7.14 (d, J=7.5Hz, 0.5H), 7.05-7.09 (m, 1H), 5.18 and 5.19 (two s, ratio 1:1, 2H).

3-(N-methylformamido)benzyl formate

A solution of 3-formamidobenzyl formate (2.068 g, 11.54 mmol) inN,N-dimethylformamide (40 mL) was treated at 23° C. and under nitrogenwith cesium carbonate (5.64 g, 17.31 mmol) followed by methyl iodide(0.80 mL, 12.8 mmol) added drop wise over 5 min. After 24 h, the solidcarbonate was filtered and the filtrate was concentrated under reducedpressure. The residual oil was chromatographed on silica gel (gradientof ethyl acetate in toluene) to give 1.780 g (80% yield) of the titlematerial as a clear oil which solidified to a white solid in the fridge.HPLC (Method A): 1.376 min. HRMS (ESI) calcd for C₁₀H₁₂NO₃ [M+H]⁺ m/z194.0812, found 194.0809. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.47 (s, 1H),8.13 (d, J=0.8 Hz, 1H), 7.40 (tr, J=7.8 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H),7.17 (br. s, 1H), 7.13 (dd, J=7.9, 2.2 Hz, 1H), 5.20 (s, 2H), 3.30 (s,3H).

(3-(Methylamino)phenyl)methanol

A solution of 3-(N-methylformamido)benzyl formate (1.76 g, 9.1 mmol) inmethanol (11 mL) was treated at 23° C. and under nitrogen with 5 Naqueous sodium hydroxide (8 mL, 40 mmol) and the resulting mixture washeated to 70° C. for 4 hours. The methanol was then evaporated underreduced pressure and the residue was diluted with saturated aqueousammonium chloride (10 mL). The aqueous phase was extracted three timeswith ether and the combined organic extract was dried over anhydroussodium sulfate and concentrated under reduced pressure to give a lightbrown oil. Distillation under vacuum (bulb to bulb distillation, bp75-85° C./0.1 torr, air bath temperature) gave 1.18 g (95% yield) of aclear oil. HPLC (Method A): 0.146 min. HRMS (ESI) calcd for C₈H₁₂NO[M+H]⁺ m/z 138.0913, found 138.088. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:6.97 (t, J=7.7 Hz, 1H), 6.46 (br. s, 1H), 6.43 (br. d, J=7 Hz, 1H),6.33-6.36 (m, 1H), 5.50 (br. s, 1H), 4.95 (t, J=5.6 Hz, 1H), 4.33 (d,J=5.6 Hz, 2H), 2.61 (s, 3H).

tert-Butyl (3-(hydroxymethyl)phenyl)(methyl)carbamate

A solution of (3-(methylamino)phenyl)methanol (1.17 g, 8.53 mmol) in drytetrahydrofuran (15 mL) was treated at 23° C. with di-tert-butyldicarbonate (2.15 g, 9.85 mmol) and the resulting mixture was stirredfor 72 hours. The reaction mixture was then concentrated under reducedpressure and the oily residue was purified by chromatography on silicagel (elution toluene-ethyl acetate 8:2) to give 1.97 g (97% yield) ofthe title material as a thick syrup. HPLC (Method A): 1.836 min. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.29 (t, J=7.8 Hz, 1H), 7.25 (br. s, 1H), 7.14(dd, J=7.8, 1.6 Hz, 2H), 4.67 (d, J=6.0 Hz, 2H), 3.24 (s, 3H), 1.74 (t,J=6.0 Hz, 1H), 1.43 (s, 9H).

tert-Butyl(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)(methyl)carbamate

A suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(2.00 g, 6.30 mmol), tert-butyl(3-(hydroxymethyl)phenyl)(methyl)carbamate (1.90 g, 8.0 mmol) andtriphenylphosphine (2.47 g, 9.41 mmol) in dry tetrahydrofuran (200 mL)was treated at 22° C. and under nitrogen with a solution of diisopropylazodicarboxylate (1.70 g, 8.40 mmol) in tetrahydrofuran (15 ml) addeddrop-wise over 2 hours. The heterogeneous mixture was homogeneous at theend of the addition and was stirred for another 3 hours. The reactionmixture was then quenched by the addition of ethyl acetate (400 mL) andsaturated sodium bicarbonate. The organic phase was washed with brine,dried over anhydrous magnesium sulfate and concentrated in vacuo.Chromatography of the residue on silica gel (elutiondichloromethane-ethyl acetate 5-10%) followed by crystallization fromethyl acetate gave 2.35 g (70% yield) of the title material as colorlesscrystals. HPLC (Method A): 2.443 min. HRMS (ESI) calcd for C₂₇H₂₉N₄O₆S[M+H]⁺ m/z 537.1802, found 537.1848. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.82(s, 1H), 7.31-7.35 (m, 2H), 7.26 (br. d, J=7.5 Hz, 1H), 7.19 (br. d,J=7.5 Hz, 1H), 7.06 (s, 1H), 6.68 (br. d, 1H),), 6.37 (d, J=1.9 Hz, 1H),5.14 (s, 2H), 4.18 (s, 3H), 3.81 (s, 3H), 3.25 (s, 3H), 1.42 (s, 9H).

Example 823-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-N-methylaniline

A solution of tert-butyl(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)(methyl)carbamate(2.20 g, 4.10 mmol) in dichloromethane (100 mL) was treated at 22° C.and under nitrogen with trifluoroacetic acid (15 mL) added drop-wiseover 5 min. After 2 hours, the solvent and excess reagent wereevaporated under reduced pressure and the residue was partitionedbetween dichloromethane and saturated sodium bicarbonate. The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give a white solid.Crystallization from 1,2-dichloroethane (10 mL, −15° C., 18 h) gave 1.66g (92% yield) of the title aniline as white cubes. HPLC (Method A):2.037 min. HRMS (ESI) calcd for C₂₂H₂₁N₄O₄S [M+H]⁺ m/z 438.1307, found438.1344. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.30 (s, 1H), 7.03 (t, J=7.8Hz, 1H), 6.89 (s, 1H), 6.73 (br. d, 1H), 6.58 (s, 1H), 6.57 (br. d, J=7Hz, 1H), 6.42 (d, J=1.8 Hz, 1H), 6.41 (br. dd, J=7, 1.5 Hz, 1H), 5.65(br. s, 1H), 5.05 (s, 2H), 4.13 (s, 3H), 3.71 (s, 3H), 2.59 (s, 3H).

Example 83N-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)-N-methylbenzamide

A solution of3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-N-methylaniline(0.100 g, 0.23 mmol) in dry tetrahydrofuran (4 mL) was treated at 22° C.and under nitrogen with 4-methylmorpholine (0.070 g, 0.69 mmol) followedby a solution of benzoyl chloride (0.040 g, 0.28 mmol) in drytetrahydrofuran (2 mL) added drop-wise over 2 min. After 1 hour, thereaction mixture was diluted with dichloromethane, washed successivelywith cold 0.1N hydrochloric acid, saturated sodium bicarbonate andbrine. After drying over anhydrous magnesium sulfate, the organic phasewas concentrated under reduced pressure. Chromatography of the residueon silica gel (elution dichloromethane-ethyl acetate 15-20%) followed bycrystallization from ethyl acetate gave 0.096 g (78% yield) of the titlematerial as colorless prisms. HPLC (Method A): 2.343 min. HRMS (ESI)calcd for C₂₉H₂₅N₄O₅S [M+H]⁺ m/z 541.154, found 541.1545. ¹H NMR (CDCl₃,400 MHz) δ ppm: 7.77 (s, 1H), 7.04-7.20 (m, 8H), 6.95 (s, 1H), 6.86-6.89(m, 1H), 6.61 (br. d, 1H), 6.19 (d, J=1.8 Hz, 1H), 4.99 (s, 2H), 4.12(s, 3H), 3.75 (s, 3H), 3.43 (s, 3H).

The following compounds were prepared using the methodology describedfor preparation of example 83

HPLC Retention Time Calc. LCMS (Min)/ [M + H]⁺ [M + H]⁺ Ex. StructureFormula Method m/z m/z NMR 84

C₃₀H₂₆N₄O₅S 2.398/B 555.1697 555.1695 ¹H NMR (CDCl₃) δ ppm: 7.87 (s,1H), 7.10-7.27 (m, 3H), 7.12 (s, 1H), 6.8-7.1 (m, 5H), 6.71 (d, J = 2Hz, 1H), 6.26 (br. s, 1H), 5.08 (br. s, 2H), 4.24 (s, 3H), 3.84 (s, 3H),3.51 (br. s, 3H), 2.29 (br. s, 3H). 85

C₂₉H₂₃FN₄O₅S 2.363/B 559.1446 559.1443 ¹H NMR (CDCl₃) δ ppm: 7.78 (s,1H), 7.19 (s, 1H), 7.16-7.19 (m, 1H), 7.09 (br. s, 1H), 7.03 (s, 1H),6.91-7.0 (m, 2H), 6.90 (s, 1H), 6.88 (br. s, 1H), 6.80 (dt, J = 8.5, 2.5Hz, 1H), 6.60 (br. d, 1H), 6.18 (d, J = 1.7 Hz, 1H), 5.02 (s, 2H), 4.15(s, 3H), 3.75 (s, 3H), 3.42 (s, 3H). 86

C₃₀H₂₆N₄O₆S 2.343/B 571.1646 571.1639 ¹H NMR (CDCl₃) δ ppm: 7.78 (s,1H), 7.0-7.2 (m, 6H), 6.90 (br. s, 1H), 6.67 (br. t, 1H), 6.60 (br. s,1H), 6.49 (br. d, 1H), 6.16 (br. s, 1H), 4.94 (br. s, 2H), 4.15 (s, 3H),3.75 (s, 3H), 3.48 (br. s, 3H), 3.42 (br. s, 3H). 87

C₂₉H₂₃FN₄O₅S 2.349/A 559.1446 559.1435 ¹H NMR (CDCl₃) δ ppm: 7.78 (s,1H), 7.15-7.2 (m, 4H), 7.09 (br. s, 1H), 6.95 (s, 1H), 6.85-6.87 (m,1H), 6.72 (br. t, J = 8.8 Hz, 2H), 6.61 (br. d, 1H), 6.16 (d, J = 1.9Hz, 1H), 5.02 (s, 2H), 4.12 (s, 3H), 3.75 (s, 3H), 3.41 (s, 3H). 88

C₂₉H₂₃FN₄O₅S 2.365/B 559.1446 559.1469 ¹H NMR (CDCl₃) δ ppm: 7.77 (s,1H), 7.0-7.18 (m, 5H), 7.00 (s, 1H), 6.93 (br. s, 1H), 6.85 (br. s, 1H),6.70 (br. s, 1H), 6.61 (s, 1H), 6.17 (br. s, 1H), 4.97 (s, 2H), 4.14 (s,3H), 3.75 (s, 3H), 3.42 (br. s, 3H). 89

C₃₀H₂₆N₄O₅S 2.427/B 555.1697 555.1728 ¹H NMR (CDCl₃) δ ppm: 7.77 (s,1H), 7.17-7.19 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.12 (br. s, 1H), 7.09(br. d, J = 8.2 Hz, 2H), 7.03 (s, 1H), 6.84-6.87 (m, 3H), 6.61 (br. d,1H), 6.21 (d, J = 1.9 Hz, 1H), 5.02 (s, 2H), 4.14 (s, 3H), 3.75 (s, 3H),3.41 (s, 3H), 2.15 (s, 3H). 90

C₂₉H₂₅N₅O₆S 2.337/B 572.1598 572.1627 ¹H NMR (CDCl₃) δ ppm: 8.07 (br. s,1H), 7.79 (s, 1H), 7.36 (br. d, 1H), 7.17-7.25 (m, 2H), 7.15 (s, 1H),7.04 (s, 1H), 6.89-6.91 (m, 1H), 6.60 (br. s, 1H), 6.40 (d, J = 9 Hz,1H), 6.21 (br. s, 1H), 5.05 (s, 2H), 4.15 (s, 3H), 3.77 (s, 3H), 3.76(s, 3H), 3.41 (s, 3H). 91

C₂₈H₂₄N₄O₆S₂ 2.326/A 577.121 577.122 ¹H NMR (CDCl₃) δ ppm: 7.77 (s, 1H),7.44-7.48 (m, 3H), 7.30-7.35 (m, 3H), 7.25 (t, J = 8 Hz, 1H), 7.02-7.04(m, 2H), 6.92 (s, 1H), 6.62 (br. d, 1H), 6.24 (d, J = 1.9 Hz, 1H), 5.03(s, 2H), 4.13 (s, 3H), 3.75 (s, 3H), 3.11 (s, 3H). 92

C₂₇H₂₂N₆O₅S 2.190/B 543.1445 543.1451 ¹H NMR (CDCl₃) δ ppm: 8.94 (br. s,1H), 8.53 (br. s, 2H), 7.80 (s, 1H), 7.22-7.28 (m, 2H), 7.16-7.18 (m,1H), 7.04 (s, 1H), 6.91-6.94 (m, 1H), 6.61 (br. d, 1H), 6.18 (d, J = 1.8Hz, 1H), 5.04 (s, 2H), 4.15 (s, 3H), 3.76 (s, 3H), 3.45 (s, 3H). 93

C₂₈H₂₅N₅O₅S₂ 2.289/B 576.137  576.1392 ¹H NMR (CDCl₃) δ ppm: 7.79 (s,1H), 7.33 (br. d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.20 (br.s, 1H), 7.05 (s, 1H), 6.96 (br. d, J = 7.5 Hz, 1H), 6.60 (br. d, 1H),6.23 (d, J = 1.8 Hz, 1H), 5.11 (s, 2H), 4.15 (s, 3H), 3.74 (s, 3H), 3.36(s, 3H), 2.42 (s, 3H), 2.38 (s, 3H). 94

C₂₄H₂₂N₄O₅S 2.232/A 479.1384 479.1375 ¹H NMR (CDCl₃) δ ppm: 7.83 (s,1H), 7.4-7.44 (m, 2H), 7.28 (s, 1H), 7.12-7.14 (m, 1H), 7.05 (s, 1H),6.68 (br. d, 1H), 6.36 (br. d, J = 1.1 Hz, 1H), 5.18 (s, 2H), 4.18 (s,3H), 3.82 (s, 3H), 3.26 (s, 3H), 1.85 (s, 3H). 95

C₂₇H₂₀F₃N₅O₅S₂ 2.053/A 616.0931 616.0969 ¹H NMR (CDCl₃) δ ppm: 7.77 (s,1H), 7.6 (br. s, 1H), 7.4-7.5 (m, 2H), 7.16 (br. s, 1H), 7.03 (s, 1H),6.98 (br. s, 1H), 6.60 (br. d, 1H), 6.21 (br. d, 1H), 5.06 (s, 2H), 4.15(s, 3H), 3.75 (s, 3H), 3.45 (s, 3H). 96

C₃₁H₂₅F₃N₄O₅S 2.150/A 623.1571 623.1612 ¹H NMR (CDCl₃) δ ppm: 8.1, 8.07,8.05, 8.0, 7.68 and 7.58 (six broad s, 1H), 7.7 (s, 1H), 7.15-7.25 (m,4H), 7.12 (br. s, 1H), 7.01 (s, 1H), 6.87-6.92 (m, 1H), 6.60 (d, J = 1.6Hz, 1H), 6.20 (d, J = 1.6 Hz, 1H), 5.01 (s, 2H), 4.15 (s, 3H), 3.75 (s,3H), 3.44 (s, 3H), 2.14 (s, 3H). 97

C₂₃H₂₀N₄O₅S 2.547/A 465.1227 465.1231 ¹H NMR (CDCl₃) δ ppm: 8.51 (s,1H), 7.86 (s, 1H), 7.37-7.48 (m, 2H), 7.30 (br. s, 1H), 7.14 (d, J = 7.8Hz, 1H), 7.08 (s, 1H), 6.72 (br. d, 1H), 6.39 (br. d, 1H), 5.21 (s, 2H),4.21 (s, 3H), 3.85 (s, 3H), 3.35 (s, 3H).

Example 98 tert-Butyl6-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indoline-1-carboxylate

Methyl indoline-6-carboxylate

A solution of methyl 1H-indole-6-carboxylate (4.80 g, 27.4 mmol) inacetic acid (40 mL) was cooled to 15° C. and then treated with sodiumcyanoborohydride (6.90 g, 0.11 mmol) added in small portions over 30min. After 5 h at 15° C., the reaction mixture was diluted with amixture of ice and water (200 mL) and carefully adjusted to pH 9-10 withsolid potassium carbonate. The aqueous phase was extracted three timeswith dichloromethane and the combined organic phase was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residual oil waschromatographed on silica gel (elution toluene-ethyl acetate 8:2) togive 3.54 g (73% yield) of the title material as yellowish solid. HPLC(Method A): 0.9 min (tailing). HRMS (ESI) calcd for C₁₀H₁₂NO₂ [M+H]⁺ m/z178.0863, found 178.0882. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.40 (dd,J=7.6, 1.5 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.12 (br. d, J=7.6 Hz, 1H),3.85 (s, 3H), 3.59 (t, J=8.5 Hz, 2H), 3.05 (t, J=8.5 Hz, 2H).

Indolin-6-ylmethanol

A solution of methyl indoline-6-carboxylate (0.830 g, 4.68 mmol) in drytetrahydrofuran (20 mL) was treated at 23° C. and under nitrogen withlithium aluminum hydride (0.23 g, 6.08 mmol) and the resulting mixturewas stirred for 3.5 h. The reaction mixture was carefully quenched bysuccessive addition of ethyl acetate (1 mL), water (0.2 mL), 15% aqueoussodium hydroxide (0.2 mL) and water (0.6 mL). The solid formed wasfiltered and the filtrate was concentrated under reduced pressure.Chromatography of the residual oil on silica gel (elution ethyl acetate)followed by distillation under vacuum (bulb to bulb distillation, bp95-105° C./0.1 torr, air bath temperature) gave 0.460 g (57% yield) of aclear oil which crystallized to a white solid. HPLC (Method A): 0.132min. HRMS (ESI) calcd for C₉H₁₂NO [M+H]⁺ m/z 150.0913, found 150.0932.¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.4 (d, J=7.4 Hz, 1H), 6.66 (dd, J=7.4,1.5 Hz, 1H), 6.63 (br. s, 1H), 4.55 (s, 2H), 3.54 (t, J=8.4 Hz, 2H),2.99 (t, J=8.4 Hz, 2H).

tert-Butyl 6-(hydroxymethyl)indoline-1-carboxylate

A solution of indolin-6-ylmethanol (0.630 g, 4.22 mmol) in drytetrahydrofuran (15 mL) was treated at 23° C. with di-tert-butyldicarbonate (0.99 g, 4.53 mmol) and the resulting mixture was stirredfor 18 hours. The reaction mixture was then concentrated under reducedpressure and the oily residue was purified by chromatography on silicagel (elution toluene-ethyl acetate 7:3) to give 1.052 g (100% yield) ofthe title material as a thick syrup which crystallized to a white solidin the fridge. HPLC (Method A): 1.905 min. ¹H NMR (CDCl₃, 400 MHz) δppm: 7.84 (br. s, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.93 (br. d, J=7.5 Hz,1H), 4.62 (d, J=6.0 Hz, 2H), 3.96 (t, J=8.7 Hz, 2H), 3.05 (t, J=8.7 Hz,2H), 1.57 (t, J=6.0 Hz, 1H), 1.54 (s, 9H).

tert-Butyl6-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indoline-1-carboxylate

A suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(0.500 g, 1.57 mmol), tert-butyl 6-(hydroxymethyl)indoline-1-carboxylate(0.500 g, 2.0 mmol) and triphenylphosphine (0.62 g, 2.36 mmol) in drytetrahydrofuran (50 mL) was treated at 22° C. and under nitrogen with asolution of diisopropyl azodicarboxylate (0.47 g, 2.32 mmol) intetrahydrofuran (10 ml) added drop-wise over 2 hours. The heterogeneousmixture was homogeneous at the end of the addition and was stirred foranother 3 hours. The reaction mixture was then quenched by the additionof ethyl acetate and saturated sodium bicarbonate. The organic phase waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. Chromatography of the residue on silica gel(elution toluene-ethyl acetate 10-15%) gave 0.582 g (67% yield) of thetitle material as a white solid. HPLC (Method A): 2.523 min. HRMS (ESI)calcd for C₂₈H₂₉N₄O₆S [M+H]⁺ m/z 549.1802, found 549.1793. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.86 (br. s, 1H), 7.74 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.98-7.04 (m, 2H), 6.59 (br. d, 1H), 6.29 (d, J=1.8 Hz, 1H),5.06 (s, 2H), 4.11 (s, 3H), 3.91 (t, J=8.7 Hz, 2H), 3.74 (s, 3H), 3.0(t, J=8.7 Hz, 2H), 1.46 (s, 9H).

Example 996-(4-(Indolin-6-ylmethoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A solution of tert-butyl6-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indoline-1-carboxylate(0.379 g, 0.69 mmol) in dichloromethane (15 mL) was treated at 22° C.and under nitrogen with trifluoroacetic acid (1.5 mL) added drop-wiseover 2 min. After 2 hours, the solvent and excess reagent wereevaporated under reduced pressure and the residue was partitionedbetween dichloromethane and saturated sodium bicarbonate. The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give 0.259 g (83% yield) of awhite solid. HPLC (Method A): 1.948 min. HRMS (ESI) calcd forC₂₃H₂₁N₄O₄S [M+H]⁺ m/z 449.1278, found 449.1284. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 7.75 (s, 1H), 7.03 (d, J=7.9 Hz, 1H), 7.01 (s, 1H), 6.71 (d,J=7.2 Hz, 1H), 6.70 (s, 1H), 6.60 (br. d, 1H), 6.31 (d, J=1.9 Hz, 1H),5.01 (s, 2H), 4.13 (s, 3H), 3.75 (s, 3H), 3.74 (br. s, 1H), 3.50 (t,J=8.3 Hz, 2H), 2.95 (t, J=8.3 Hz, 2H).

Example 100(6-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indolin-1-yl)(phenyl)methanone

A solution of6-(4-(indolin-6-ylmethoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.065 g, 0.145 mmol) in dry tetrahydrofuran (4 mL) was treated at 22°C. and under nitrogen with 4-methylmorpholine (0.050 g, 0.49 mmol)followed by a solution of benzoyl chloride (0.025 g, 0.18 mmol) in drytetrahydrofuran (1 mL) added drop-wise over 2 min. After 1 hour, thereaction mixture was diluted with dichloromethane, washed successivelywith cold 0.1N hydrochloric acid, saturated sodium bicarbonate andbrine. After drying over anhydrous magnesium sulfate, the organic phasewas concentrated under reduced pressure. Chromatography of the residueon silica gel (elution dichloromethane-ethyl acetate 10-15%) gave 0.053g (66% yield) of the title material as a white solid. HPLC (Method A):2.354 min. HRMS (ESI) calcd for C₃₀H₂₅N₄O₅S [M+H]⁺ m/z 553.154, found553.154. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.76 (s, 1H), 7.4-7.5 (m, 2H),7.3-7.4 (m, 3H), 7.13 (br. d, J=7.0 Hz, 1H), 7.08 (br. s, 2H), 6.94 (br.s, 1H), 6.65 (br. s, 1H), 6.24 (br. s, 1H), 5.05 (br. s, 2H), 4.12 (s,3H), 4.03 (br. s, 2H), 3.75 (s, 3H), 3.04 (t, J=8.3 Hz, 2H).

The following compounds were prepared using the methodology describedfor preparation of example 100

HPLC Retention Calc. LCMS Time (Min)/ [M + H]⁺ [M + H]⁺ Ex. StructureFormula Method m/z m/z NMR 101

C₃₁H₂₆N₄O₅S 2.495/B 567.1697 567.1704 ¹H NMR (CDCl₃) δ ppm: (mixture ofrotamers) 8.47 (br. s, 0.7H), 7.88 (br. s, 1.2 H), 7.2-7.4 (m, 4H),7.0-7.15 (m, 1.6H), 6.69 and 6.67 (two s, 1.1H), 6.44 (s, 0.7H), 6.10(s, 0.6H), 5.67 (s, 0.65H), 5.24 (s, 1.3H), 4.84 (s, 1H), 4.34 (br. t,1H), 4.25 (s, 3H), 3.86 and 3.83 (two s, 3H), 3.75-3.83 (m, 1.4H),3.10-3.2 (m, 2H), 2.16 and 2.39 (two s, 3H). 102

C₃₀H₂₃FN₄O₅S 2.017/A 571.1446 571.1453 ¹H NMR (CDCl₃) δ ppm: 7.76 (s,1H), 7.31 (br. s, 1H), 7.24 (br. s, 1H), 7.06-7.22 (m, 4H), 7.05 (br. t,1H), 6.95 (br. s, 1H), 6.60 (br. d, 1H), 6.25 (br. s, 1H), 5.02 (br. s,2H), 4.12 (s, 3H), 4.0 (br. s, 2H), 3.75 (s, 3H), 3.05 (t, J = 8.3 Hz,2H). 103

C₃₁H₂₆N₄O₆S 1.999/A 583.1646 583.1658 ¹H NMR (CDCl₃) δ ppm: (mixture ofrotamers) 8.36 (s, 0.7H), 7.75 and 7.77 (two s, 1H), 7.05-7.35 (m, 3H),7.01 (s, 0.7H), 6.95 (t, J = 7.5 Hz, 0.7H), 6.85-6.9 (m, 2H), 6.65 (d, J= 8 Hz, 0.3H), 6.55-6.55 (m, 1H), 6.34 (s, 0.7H), 6.04 (s, 0.3H), 5.82(s, 0.3H), 5.13 (s, 1.3H), 4.77 (s, 0.6H), 4.2-4.35 (m, 0.6H), 4.11 and4.13 (two s, 3H), 3.7-3.8 (m, 7H), 3.44 (s, 0.9H), 3.01 (br. t, J = 8.4Hz, 2H). 104

C₃₀H₂₃FN₄O₅S 2.042/A 571.1446 571.1447 ¹H NMR (CDCl₃) δ ppm: (mixture ofrotamers) 8.33 (s, 0.8H), 7.76 (broad s, 1H), 6.9-7.4 (m, 7H), 6.61 (br.s, 1H), 6.34 (s, 0.8H), 5.95 and 6.06 (two br. s, 0.4H), 5.14 and 4.78(two s, 2H), 4.32 and 4.18 (two br. s, 0.6H), 4.12 (s, 3H), 3.8 (t, J =8.2 Hz, 1.4H), 3.76 and 3.74 (two s, 3H), 3.06 (br. t, J = 8.2 Hz, 2H).105

C₃₁H₂₆N₄O₅S 2.083/A 567.1697 567.1698 ¹H NMR (CDCl₃) δ ppm: 7.76 (s,1H), 7.37 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.1-7.15(m,2H), 7.09 (br. s, 1H), 6.96 (br. s, 1H), 6.60 (br. d, 1H), 6.26 (br. s,1H), 5.01 (br. s, 2H), 4.12 (s, 3H), 4.04 (br. t, 2H), 3.75 (s, 3H),3.03 (t, J = 8.3 Hz, 2H), 2.28 (br. s, 3H). 106

C₃₀H₂₅N₅O₆S 2.000/A 584.1598 584.1601 ¹H NMR (CDCl₃) δ ppm: 8.38 (d, J =1.6 Hz, 1H), 7.77 (s, 1H), 7.72 (dd, J = 8.2, 2.1 Hz, 1H), 7.08-7.15 (m,2H), 6.99 (s, 1H), 6.59 (br. d, 1H), 6.30 (d, J = 1.9 Hz, 1H), 5.06 (br.s, 2H), 4.13 (s, 3H), 4.08 (t, J = 8.2 Hz, 2H), 3.89 (s, 3H), 3.76 (s,3H), 3.07 (t, J = 8.2 Hz, 2H). 107

C₂₅H₂₂N₄O₅S 2.266/A 491.1384 491.1389 ¹H NMR (CDCl₃) δ ppm: 8.31 (s,1H), 7.84 (s, 1H), 7.15-7.22 (m, 2H), 7.09 (s, 1H), 6.69 (br. d, 1H),6.40 (d, J = 1.6 Hz, 1H), 5.17 (s, 2H), 4.21 (s, 3H), 4.09 (t, J = 8.5Hz, 2H), 3.84 (s, 3H), 3.21 (t, J = 8.5 Hz, 2H), 2.25 (s, 3H). 108

C₂₈H₂₂N₆O₅S 1.935/A 555.1445 555.1449 ¹H NMR (CDCl₃) δ ppm: 9.25 (s,1H), 8.90 (s, 2H), 8.25 (br. s, 1H), 7.77 (broad s, 1H), 7.15-7.2 (m,2H), 6.99 (br. s, 1H), 6.61 (s, 1H), 6.30 (br. s, 1H), 5.12 (br. s, 2H),4.12 (s, 3H), 3.90-4.1 (m, 2H), 3.76 (s, 3H), 3.12 (t, J = 8.2 Hz, 2H).109

C₂₉H₂₅N₅O₅S₂ 1.992/A 588.137 588.1386 ¹H NMR (CDCl₃) δ ppm: 7.77 (s,1H), 7.15- 7.2 (m, 3H), 6.99 (s, 1H), 6.61 (d, J = 2H, 1H), 6.28 (d, J =2 Hz, 1H), 5.06 (s, 2H), 4.12 (s, 3H), 4.05 (t, J = 8.2 Hz, 2H), 3.76(s, 3H), 3.08 (t, J = 8.2 Hz, 2H), 2.60 (s, 3H), 2.38 (s, 3H). 110

C₂₈H₂₀F₃N₅O₅S₂ 2.382/A 628.0931 628.0951 ¹H NMR (CDCl₃) δ ppm: 8.35 (d,J = 7.4 Hz, 2H), 7.75 (s, 1H), 7.15-7.22 (m, 2H), 7.01 (s, 1H), 6.60 (s,1H), 6.30 (br. s, 1H), 5.12 (s, 2H), 4.54 (br. t, J = 8.2 Hz, 2H), 4.12(s, 3H), 3.75 (s, 3H), 3.15 (t, J = 8.2 Hz, 2H). 111

C₃₂H₂₅F₃N₄O₅S 2.274/A 635.1571 635.1589 ¹H NMR (CDCl₃) δ ppm: (mixtureof rotamers) 8.11, 8.07, 8.05 and 8.0 (four s, 0.6H), 7.76 ( broad s,1H), 7.4-7.7 (m, 4H), 7.15-7.20 (m, 2H), 7.05 (br. s, 1H), 6.59 (s, 1H),6.30 (br. s, 1H), 5.08 (br. s, 1H), 4.14 (s, 3H), 4.0 (br. s, 2H), 3.76(s, 3H), 3.07 (t, J = 8.2 Hz, 2H), 2.36 br. s, 3H). 112

C₃₃H₂₅N₅O₅S₂ 2.587/A 636.137 636.1378 ¹H NMR (CDCl₃) δ ppm: 8.39 (br. s,1H), 8.36 (broad s, 1H), 7.90 (br. s, 2H), 7.75 (s, 1H), 7.39 (br. s,3H), 7.15-7.2 (m, 2H), 7.01 (br. s, 1H), 6.60 (s, 1H), 6.33 (br. s, 1H),5.13 (br. s, 2H), 4.62 (br. t, 2H), 4.12 (s, 3H), 3.75 (s, 3H), 3.15 (t,J = 8.4 Hz, 2H).

Example 113 tert-Butyl4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indoline-1-carboxylate

Methyl indoline-4-carboxylate

A solution of methyl 1H-indole-4-carboxylate (2.60 g, 14.84 mmol) inacetic acid (26 mL) was cooled to 15° C. and then treated with sodiumcyanoborohydride (3.82 g, 0.061 mmol) added in small portions over 30min. After 5 h at 15° C., the reaction mixture was diluted with amixture of ice and water (200 mL) and carefully adjusted to pH 9-10 withsolid potassium carbonate. The aqueous phase was extracted three timeswith dichloromethane and the combined organic phase was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residual oil waschromatographed on silica gel (elution dichloromethane-ethyl acetate5-10%) to give 1.26 g (48% yield) of the title material as white solid.HPLC (Method A): 0.9 min (tailing). HRMS (ESI) calcd for C₁₀H₁₂NO₂[M+H]⁺ m/z 178.0863, found 178.0867. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.32(br. d, J=7.9 Hz, 1H), 7.05 (br. t, J=8 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H),3.86 (s, 3H), 3.57 (t, J=8.4 Hz, 2H), 3.37 (t, J=8.4 Hz, 2H).

Indolin-4-ylmethanol

A solution of methyl indoline-4-carboxylate (1.20 g, 6.77 mmol) in drytetrahydrofuran (20 mL) was treated at 23° C. and under nitrogen withlithium aluminum hydride (0.35 g, 6.08 mmol) added in small portionsover 20 min and the resulting mixture was stirred for 3 h. The reactionmixture was carefully quenched by successive addition of ethyl acetate(1 mL), water (0.4 mL), 15% aqueous sodium hydroxide (0.4 mL) and water(1.2 mL). The solid formed was filtered and the filtrate wasconcentrated under reduced pressure. Chromatography of the residual oilon silica gel (elution ethyl acetate) followed by distillation undervacuum (bulb to bulb distillation, bp 105-110° C./0.1 torr, air bathtemperature) gave 0.62 g (61% yield) of a white solid. HPLC (Method A):0.13 min. HRMS (ESI) calcd for C₉H₁₂NO [M+H]⁺ m/z 150.0913, found150.0932. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.05 (t, J=7.6 Hz, 1H), 6.74(d, J=7.1 Hz, 1H), 6.62 (d, J=7.7 Hz, 1H), 4.64 (s, 2H), 3.60 (t, J=8.4Hz, 2H), 3.06 (t, J=8.4 Hz, 2H).

tert-Butyl 4-(hydroxymethyl)indoline-1-carboxylate

A solution of indolin-4-ylmethanol (0.57 g, 3.82 mmol) in drytetrahydrofuran (15 mL) was treated at 23° C. with di-tert-butyldicarbonate (0.92 g, 4.2 mmol) and the resulting mixture was stirred for18 hours. The reaction mixture was then concentrated under reducedpressure and the residue was purified by chromatography on silica gel(elution toluene-ethyl acetate 7:3) to give 0.95 g (100% yield) of thetitle material as a thick syrup which crystallized to a white solid inthe fridge. HPLC (Method A): 1.901 min. ¹H NMR (CDCl₃, 400 MHz) δ ppm:7.8 (br. s, 1H), 7.19 (t, J=7.9 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 4.64(d, J=5.9 Hz, 2H), 4.01 (br. t, J=8.7 Hz, 2H), 3.11 (t, J=8.7 Hz, 2H),1.58 (s, 9H).

tert-Butyl4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indoline-1-carboxylate

A suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(0.529 g, 1.67 mmol), tert-butyl 6-(hydroxymethyl)indoline-1-carboxylate(0.462 g, 1.85 mmol) and triphenylphosphine (0.66 g, 2.5 mmol) in drytetrahydrofuran (40 mL) was treated at 22° C. and under nitrogen with asolution of diisopropyl azodicarboxylate (0.41 g, 2.0 mmol) intetrahydrofuran (10 ml) added drop-wise over 2 hours. The heterogeneousmixture was homogeneous at the end of the addition and was stirred foranother 3 hours. The reaction mixture was then quenched by the additionof ethyl acetate and saturated sodium bicarbonate. The organic phase waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. Chromatography of the residue on silica gel(elution dichloromethane-ethyl acetate 2-5%) followed by crystallizationfrom ethyl acetate gave 0.621 g (68% yield) of the title material as awhite solid. HPLC (Method A): 2.543 min. HRMS (ESI) calcd forC₂₈H₂₉N₄O₆S [M+H]⁺ m/z 549.1802, found 549.182. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 7.7-8.0 (br. s, 1H), 7.84 (s, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.07(d, J=7.8 Hz, 1H), 7.05 (s, 1H), 6.70 (br. d, 1H), 6.39 (d, J=2.0 Hz,1H), 5.12 (s, 2H), 4.21 (s, 3H), 4.02 (br. t, 2H), 3.85 (s, 3H), 3.16(t, J=8.6 Hz, 2H), 1.58 (s, 9H).

Example 1146-(4-(Indolin-4-ylmethoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A suspension of tert-butyl4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indoline-1-carboxylate(0.600 g, 1.09 mmol) in dichloromethane (20 mL) was treated at 22° C.and under nitrogen with trifluoroacetic acid (5 mL) added drop-wise over2 min and the resulting solution was stirred for 2 hours. The solventand excess reagent were evaporated under reduced pressure and theresidue was partitioned between dichloromethane and saturated sodiumbicarbonate. The organic phase was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive 0.490 g (99% yield) of a white solid. HPLC (Method A): 1.981 min.HRMS (ESI) calcd for C₂₃H₂₁N₄O₄S [M+H]⁺ m/z 449.1278, found 449.1293. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 7.84 (s, 1H), 7.07 (s, 1H), 7.06 (t, J=7.8Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.69 (br. d, 1H), 6.65 (d, J=7.9 Hz,1H), 6.42 (d, J=1.9 Hz, 1H), 5.12 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H),3.50 (t, J=8.4 Hz, 2H), 3.12 (t, J=8.4 Hz, 2H).

Example 115(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)indolin-1-yl)(phenyl)methanone

A solution of6-(4-(indolin-4-ylmethoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.080 g, 0.178 mmol) in dry tetrahydrofuran (5 mL) was treated at 22°C. and under nitrogen with 4-methylmorpholine (0.054 g, 0.535 mmol)followed by a solution of benzoyl chloride (0.030 g, 0.23 mmol) in drytetrahydrofuran (1 mL) added drop-wise over 2 min. After 1 hour, thereaction mixture was diluted with dichloromethane, washed successivelywith cold 0.1N hydrochloric acid, saturated sodium bicarbonate andbrine. After drying over anhydrous magnesium sulfate, the organic phasewas concentrated under reduced pressure. Chromatography of the residueon silica gel (elution dichloromethane-ethyl acetate 5-15%) gave 0.087 g(84% yield) of the title material as a white solid. HPLC (Method A):2.449 min. HRMS (ESI) calcd for C₃₀H₂₅N₄O₅S [M+H]⁺ m/z 553.154, found553.155. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.84 (s, 1H), 7.54-7.6 (m, 2H),7.4-7.5 (m, 3H), 7.1-7.3 (m, 3H), 7.04 (d, J=0.8 Hz, 1H), 6.71 (br. d,1H), 6.40 (d, J=2.0 Hz, 1H), 5.15 (s, 2H), 4.21 (s, 3H), 4.12 (br. s,2H), 3.85 (s, 3H), 3.20 (t, J=8.2 Hz, 2H).

The following compounds were prepared using the methodology describedfor preparation of Example 115

HPLC Retention Calc. LCMS Time (Min)/ [M + H]⁺ [M + H]⁺ Ex. StructureFormula Method m/z m/z NMR 116

C₃₀H₂₃FN₄O₅S 2.394/A 571.1446 571.1462 ¹H NMR (CDCl₃) δ ppm: 7.85 (s,1H), 7.55- 7.65 (m, 2H), 7.11-7.21 (m, 5H), 7.04 (s, 1H), 6.70 (br. d,1H), 6.40 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H), 4.21 (s, 3H), 4.12 (br. t,2H), 3.85 (s, 3H), 3.21 (t, J = 8.2 Hz, 2H). 117

C₂₅H₂₂N₄O₅S 2.285/A 491.1384 491.1401 ¹H NMR (CDCl₃) δ ppm: 8.09 (d, J =8.2 Hz, 1H), 7.75 (s, 1H), 7.12 (br. t, J = 7.8 Hz, 1H), 7.03 (d, J =7.8 Hz, 1H), 6.91 (s, 1H), 6.58 (br. d, 1H), 6.29 (d, J = 1.6 Hz, 1H),5.03 (s, 2H), 4.11 (s, 3H), 4.0 (t, J = 8.5 Hz, 2H), 3.73 (s, 3H), 3.17(t, J = 8.5 Hz, 2H), 2.13 (s, 3H). 118

C₂₈H₂₀F₃N₅O₅S₂ 2.185/A 628.0931 628.0946 ¹H NMR (CDCl₃) δ ppm: 8.35 (br.s, 1H), 8.24 (br. d, J = 9 Hz, 1H), 7.76 (s, 1H), 7.23 (br. t, J = 7.8Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.96 (s, 1H), 6.62 (br. d, 1H), 6.32(d, J = 2.0 Hz, 1H), 5.09 (s, 2H), 4.52 (t, J = 8.2 Hz, 2H), 4.12 (s,3H), 3.76 (s, 3H), 3.21 (t, J = 8.2 Hz, 2H). 119

C₃₃H₂₅N₅O₅S₂ 2.328/A 636.137 636.1383 ¹H NMR (CDCl₃) δ ppm: 8.27 (br. s,1H), 8.07 (br. s, 1H), 7.85-7.95 (m, 2H), 7.76 (s, 1H), 7.35-7.45 (m,3H), 7.15-7.25 (m, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.98 (s, 1H), 6.62(br. d, 1H), 6.33 (d, J = 1.5 Hz, 1H), 5.1 (s, 2H), 4.64 (br. t, 2H),4.12 (s, 3H), 3.77 (s, 3H), 3.22 (t, J = 8.2 Hz, 2H). 120

C₃₀H₂₃FN₄O₅S 2.030/A 571.1446 571.1465 ¹H NMR (CDCl₃) δ ppm: 8.24 (br.d, J = 7.4 Hz, 1H), 7.75 (s, 1H), 7.3-7.45 (m, 2H), 7.2- 7.25 (m, 1H),7.13-7.18 (m, 2H), 7.07 (t, J = 9.0 Hz, 1H), 6.94 (s, 1H), 6.61 (br. d,1H), 6.29 (d, J = 1.9 Hz, 1H), 5.07 (s, 2H), 4.12 (s, 3H), 3.88 (t, J =8.2 Hz, 2H), 3.76 (s, 3H), 3.13 (t, J = 8.5 Hz, 2H). 121

C₃₀H₂₃FN₄O₅S 2.045/A 571.1446 571.1455 ¹H NMR (CDCl₃) δ ppm: 8.1 (br. s,1H), 7.76 (s, 1H), 7.3-7.38 (m, 1H), 7.26 (br. d, J = 7.6 Hz, 1H),7.15-7.2 (m, 2H), 7.08- 7.12 (m, 2H), 6.95 (s, 1H), 6.61 (br. d, 1H),6.31 (d, J = 2.0 Hz, 1H), 5.07 (s, 2H), 4.12 (s, 3H), 4.02 (br. t, 2H),3.76 (s, 3H), 3.12 (t, J = 8.3 Hz, 2H). 122

C₃₁H₂₆N₄O₅S 2.136/A 567.1697 567.1695 ¹H NMR (CDCl₃) δ ppm: (mixture ofrotamers) 8.31 (br. d, J = 8.2 Hz, 0.5H), 7.93 (br. dd, J = 8.3, 1.6 Hz,0.2H), 7.05-7.4 (m, 7H), 6.95 (br. s, 1H), 6.75 (br. s, 0.3H), 6.62 (br.s, 1H), 6.31 (d, J = 2 Hz, 1H), 5.56 (br. s, 0.3 H), 5.05 (br. s, 2H),4.27 and 3.68 (two br. t, 2H), 4.12 (s, 3H), 3.76 (s, 3H), 3.1 (br. t,2H), 2.19 and 2.3 (two broad s, 3H). 123

C₃₁H₂₆N₄O₅S 2.125/A 567.1697 567.1693 ¹H NMR (CDCl₃) δ ppm: 7.75 (s,1H), 7.38 (d, J = 8.1 Hz, 2H), 7.1-7.2 (m, 4H), 7.06 (br. s, 1H), 6.95(s, 1H), 6.61 (br. d, 1H), 6.31 (d, J = 1.6 Hz, 1H), 5.06 (br. s, 2H),4.12 (s, 3H), 4.04 (br. t, J = 8 Hz, 2H), 3.76 (s, 3H), 3.1 (t, J = 8.1Hz, 2H), 2.33 (s, 3H). 124

C₃₁H₂₆N₄O₆S 2.042/A 583.1646 583.1634 ¹H NMR (CDCl₃) δ ppm: (mixture ofrotamers) 8.29 (br. d, J = 7.9 Hz, 0.7H), 7.75 (s, 1H), 7.2-7.4 (m, 3H), 7.10 (d, J = 7.8 Hz, 0.7H), 6.9-7.0 (m, 2.3H), 6.87 (d, J = 8.3 Hz,1H), 6.75 (br. s, 0.3H), 6.61 (br. s, 1H), 6.31 (br.s, 1H), 5.05 (s,2H), 4.2 and 3.8 (two br. s, 2H), 4.12 (s, 3H), 3.78 (s, 3H), 3.76 (s,3H), 3.08 (br. t, J = 8.3 Hz, 2H). 125

C₃₂H₂₅F₃N₄O₅S 2.163/A 635.1571 635.157 ¹H NMR (CDCl₃) δ ppm: 8.2 (br. s,1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.47 (br. s, 2H), 7.1-7.2 (m, 2H), 6.95(s, 1H), 6.61 (br. d, 1H), 6.31 (d, J = 1.6 Hz, 1H), 5.07 (s, 2H), 4.12(s, 3H), 3.98 (br. s, 2H), 3.76 (s, 3H), 3.13 (t, J = 8.2 Hz, 2H), 2.39(s, 3H). 126

C₂₈H₂₂N₆O₅S 1.926/A 555.1445 555.1431 ¹H NMR (CDCl₃) δ ppm: 9.25 (s,1H), 8.89 (s, 2H), 8.15 (br. s, 1H), 7.75 (s, 1H), 7.0- 7.25 (m, 2H),6.94 (s, 1H), 6.62 (br. d, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.09 (s, 2H),4.12 (s, 3H), 4.06 (br. s, 2H), 3.76 (s, 3H), 3.19 (t, J = 8.2 Hz, 2H).127

C₃₀H₂₅N₅O₆S 2.005/A 584.1598 584.1595 ¹H NMR (CDCl₃) δ ppm: 8.36 (d, J =2.3 Hz, 2H), 7.76 (s, 1H), 7.73 (dd, J = 8.6, 2.3 Hz, 1H), 7.07-7.18 (m,2H), 6.95 (s, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.61 (br. d, 1H), 6.31 (d,J = 1.8 Hz, 1H), 5.07 (s, 2H), 4.12 (s, 3H), 4.08 (t, J = 8.2 Hz, 2H),3.92 (s, 3H), 3.76 (s, 3H), 3.13 (t, J = 8.2 Hz, 2H). 128

C₂₈H₂₂N₆O₅S 1.880/A 555.1445 555.1435 ¹H NMR (CDCl₃) δ ppm: 9.30 (d, J =5 Hz, 1H), 9.29 (s, 1H), 8.15 (br. s, 1H), 7.76 (s, 1H), 7.54 (dd, J =5, 2.4 Hz, 1H), 7.25 (br. s, 1H), 7.1-7.2 (m, 1H), 6.92 (s, 1H), 6.62(br. d, 1H), 6.30 (d, J = 1.5 Hz, 1H), 5.08 (s, 2H), 4.13 (s, 3H), 3.95(br. s, 2H), 3.76 (s, 3H), 3.19 (t, J = 8.4 Hz, 2H). 129

C₂₉H₂₅N₅O₅S₂ 2.043/A 588.137 588.1355 ¹H NMR (CDCl₃) δ ppm: 7.76 (s,1H), 7.7 (br. s, 1H), 7.1-7.2 (m, 2H), 6.92 (s, 1H), 6.62 (br. d, 1H),6.31 (d, J = 2.0 Hz, 1H), 5.06 (s, 2H), 4.13 (s, 3H), 4.05 (t, J = 8.3Hz, 2H), 3.77 (s, 3H), 3.15 (t, J = 8.3 Hz, 2H), 2.64 (s, 3H), 2.39 (s,3H). 130

C₃₂H₂₃F₅N₄O₆S 2.074/A 687.1331 687.1334 ¹H NMR (CDCl₃) δ ppm: 8.1 (br.s, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.1-7.2(m, 2H), 6.95 (s, 1H), 6.62 (br. d, 1H), 6.52 (t, J = 72 Hz, 1H), 6.31(d, J = 2.0 Hz, 1H), 5.07 (s, 2H), 4.12 (s, 3H), 3.98 (br. s, 2H), 3.76(s, 3H), 3.1 (t, J = 8.2 Hz, 2H). 131

C₃₁H₂₅FN₄O₅S 2.109/A 585.1602 585.1605 ¹H NMR (CDCl₃) δ ppm: (mixture ofrotamers) 8.33 (br. d, J = 7.1 Hz, 0.5H), 7.82 (s, 1H), 7.2-7.4 (m,2.5H), 7.0-7.15 (m, 3.5H), 6.85 (br. s, 0.5H), 6.68 (br. s, 1H), 6.37(d, J = 1.5 Hz, 1H), 5.28 (br. s, 2H), 4.32 and 3.76 (two br. t, 2H),4.19 (s, 3H), 3.83 (s, 3H), 3.15-3.23 (m, 2H), 2.2 and 2.32 (two broads, 3H).

General Synthetic Procedure for Examples 132-166

Procedure:

Into a reaction vessel containing acylating reagent (0.091 mmol) wasadded3-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)aniline(Example 4, 18 mg, 0.043 mmol) dissolved in THF (0.076 M) andN-methylmorpholine (20 μl, 0.182 mmol). The reaction mixture was stirredat rt for 3 h. Upon complete conversion as monitored by LC-MS, to thereaction mixture was added water (0.1 mL), acetic acid (5 μl) and DMF(0.5 mL). The reaction mixture was subjected to reverse-phase HPLCpurification to afford the desired product.

Purification:

The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×100 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile: water with 0.05% TFA. Gradient: 0-100% B over 15 minutes;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation.

QC Analysis: Analytical Method G:

Column: Supelco Ascentris Express 4.6×50 mm, 2.7 m particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5acetonitrile:water with 10 mM NH4OAc; Gradient: 0-100% B over 4 minutes,4.0 mL/min; Detection: UV at 220 nm.

Ana- Ex- Ob- lyt- am- % HPLC served ical ple # Structure FW Purity RT MSIon Method 132

529.57 98.95 2.93 530.04 G 133

528.54 100.00 2.70 529.00 G 134

516.53 95.10 2.74 517.01 G 135

540.59 98.33 2.92 541.07 G 136

492.55 97.72 2.76 493.06 G 137

586.62 96.69 3.02 587.08 G 138

532.61 98.41 3.11 533.10 G 139

527.55 98.38 3.00 528.03 G 140

612.55 90.68 3.25 613.05 G 141

612.55 100.00 3.07 613.05 G 142

612.55 98.30 3.36 613.05 G 143

562.54 95.62 2.91 563.04 G 144

569.63 92.71 3.08 570.10 G 145

518.58 96.32 2.99 519.09 G 146

546.64 98.10 3.23 547.12 G 147

612.55 97.37 3.02 613.06 G 148

527.55 100.00 2.55 528.02 G 149

594.56 97.37 3.25 595.03 G 150

532.61 98.88 3.12 533.10 G 151

579.00 100.00 3.16 579.01 G 152

562.54 94.40 3.05 563.04 G 153

594.56 98.93 3.24 595.05 G 154

562.54 93.83 3.05 563.04 G 155

517.51 96.05 2.68 518.00 G 156

595.45 97.45 3.13 594.98 G 157

624.59 98.83 3.21 625.10 G 158

602.66 97.95 3.40 603.10 G 159

562.54 97.47 3.13 563.03 G 160

556.59 95.06 2.98 557.03 G 161

612.55 98.67 3.32 613.03 G 162

586.62 97.75 2.78 587.08 G 163

558.58 100.00 3.16 559.06 G 164

592.57 96.58 3.05 593.05 G 165

534.58 97.36 2.53 535.06 G 166

562.54 100.00 3.10 563.04 G

Biology

The term “PAR4 antagonist” denotes an inhibitor of platelet aggregationwhich binds PAR4 and inhibits PAR4 cleavage and/or signaling. Typically,PAR4 activity is reduced in a dose dependent manner by at least 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to suchactivity in a control cell. The control cell is a cell that has not beentreated with the compound. PAR4 activity is determined by any standardmethod in the art, including those described herein (for example calciummobilization in PAR4 expressing cells, platelet aggregation, plateletactivation assays measuring e.g., calcium mobilization, p-selectin orCD40L release, or thrombosis and hemostasis models). The term “PAR4antagonist” also includes a compound that inhibits both PAR1 and PAR4.

It is desirable to find compounds with advantageous and improvedcharacteristics compared with known anti-platelet agents, in one or moreof the following categories that are given as examples, and are notintended to be limiting: (a) pharmacokinetic properties, including oralbioavailability, half life, and clearance; (b) pharmaceuticalproperties; (c) dosage requirements; (d) factors that decrease bloodconcentration peak-to-trough characteristics; (e) factors that increasethe concentration of active drug at the receptor; (f) factors thatdecrease the liability for clinical drug-drug interactions; (g) factorsthat decrease the potential for adverse side-effects, includingselectivity versus other biological targets; (h) improved therapeuticindex with less propensity for bleeding; and (h) factors that improvemanufacturing costs or feasibility.

The term “compound”, as used herein, means a chemical, be itnaturally-occurring or artificially-derived. Compounds may include, forexample, peptides, polypeptides, synthetic organic molecules, naturallyoccurring organic molecules, nucleic acid molecules, peptide nucleicacid molecules, and components and derivatives thereof.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or nonhumanorganism that could potentially benefit from treatment with a PAR4antagonist. Exemplary subjects include human beings of any age with riskfactors for cardiovascular disease, or patients that have alreadyexperienced one episode of cardiovascular disease. Common risk factorsinclude, but are not limited to, age, male sex, hypertension, smoking orsmoking history, elevation of triglycerides, elevation of totalcholesterol or LDL cholesterol.

In some embodiments, the subject is a species having a dual PAR1/PAR4platelet receptor repertoire. As used herein, the term “dual PAR1/PAR4platelet receptor repertoire” means that a subject expresses PAR1 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR1/PAR4 platelet receptor repertoire include human beings, non-humanprimates, and guinea pigs.

In other embodiments, the subject is a species having a dual PAR3/PAR4platelet receptor repertoire. As used herein, the term “dual PAR3/PAR4platelet receptor repertoire” means that a subject expresses PAR3 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR3/PAR4 platelet receptor repertoire include rodents and rabbits.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting its development; and/or(b) relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit and/or antagonize PAR4 and/or toprevent or treat the disorders listed herein. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi) within a blood vessel that may causeischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population. (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl.J. Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA,293(6):715-722 (2005).) Hence, the most common cancers associated withthrombosis in men are prostate, colorectal, brain, and lung cancer, andin women are breast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular weight heparin preparations have been approvedby the FDA for these indications.

The term “pharmaceutical composition”, as used herein, means anycomposition, which contains at least one therapeutically or biologicallyactive agent and is suitable for administration to the patient. Any ofthese formulations can be prepared by well-known and accepted methods ofthe art. See, for example, Gennaro, A. R., ed., Remington: The Scienceand Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa.(2000).

The invention includes administering to a subject a pharmaceuticalcomposition that includes a compound that binds to PAR4 and inhibitsPAR4 cleavage and/or signaling (referred to herein as a “PAR4antagonist” or “therapeutic compound”).

The compounds of this disclosure can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The preferred dose of the PAR4 antagonist is a biologically active dose.A biologically active dose is a dose that will inhibit cleavage and/orsignaling of PAR4 and have an anti-thrombotic effect. Desirably, thePAR4 antagonist has the ability to reduce the activity of PAR4 by atleast 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or morethan 100% below untreated control levels. The levels of PAR4 inplatelets is measured by any method known in the art, including, forexample, receptor binding assay, platelet aggregation, plateletactivation assays (e.g., p-selectin expression by FACS), Western blot orELISA analysis using PAR4 cleavage sensitive antibodies. Alternatively,the biological activity of PAR4 is measured by assessing cellularsignaling elicited by PAR4 (e.g., calcium mobilization or other secondmessenger assays).

In some embodiments, a therapeutically effective amount of a PAR4compound is preferably from about less than 100 mg/kg, 50 mg/kg, 10mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more preferredembodiment, the therapeutically effective amount of the PAR4 compound isless than 5 mg/kg. In a most preferred embodiment, the therapeuticallyeffective amount of the PAR4 compound is less than 1 mg/kg. Effectivedoses vary, as recognized by those skilled in the art, depending onroute of administration and excipient usage.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration may contain a water soluble saltof the active ingredient, suitable stabilizing agents, and if necessary,buffer substances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Dispersion

A spray dried dispersion can be prepared for oral administration bymethods know to one skilled in the art.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, or Formula IA, or FormulaIB, or Formula IC, or Formula ID, or Formula IE, or Formula IF, orFormula IG, or Formula IH, or Formula IJ, or Formula IN, or Formula IO,or Formula IP, or Formula IQ, or Formula IR, or a compound selected fromone of the examples, generally the amount of each component in a typicaldaily dosage and typical dosage form may be reduced relative to theusual dosage of the agent when administered alone, in view of theadditive or synergistic effect of the therapeutic agents whenadministered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the examples and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Additionally, certain compounds disclosed herein may be useful asmetabolites of other compounds. Therefore, in one embodiment, compoundsmay be useful either as a substantially pure compound, which may alsothen be incorporated into a pharmaceutical composition, or may be usefulas metabolite which is generated after administration of the prodrug ofthat compound. In one embodiment, a compound may be useful as ametabolite by being useful for treating disorders as described herein.

The activity of the PAR4 antagonists of the present invention can bemeasured in a variety of in vitro assays. Exemplary assays are shown inthe Examples below.

The FLIPR assay is an exemplary in vitro assay for measuring theactivity of the PAR4 antagonists of the present invention. In thisassay, intracellular calcium mobilization is induced in PAR4 expressingcells by a PAR4 agonist and calcium mobilization is monitored. See,e.g., Example A.

AYPGKF is a known PAR4 agonist. An alternative PAR4 agonist isH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂.H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ has improved agonistactivity as compared to AYPGKF with an EC₅₀ that is 10 fold lower thanthe EC₅₀ for AYPGKF in the FLIPR assay.H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ can be synthesizedusing methods well known to those of skill in the art.

The FLIPR assay can also be used as a counterscreen to test agonistactivity or PAR1 antagonist activity in a cell line that expresses bothPAR1 and PAR4. The PAR1 antagonist activity can be tested by the abilityof the compound to inhibit calcium mobilization induced by the PAR1agonist peptide SFLLRN or other PAR1 agonist peptides.

The compounds of the current invention can be tested in vitro for theirability to inhibit platelet aggregation induced by gamma-thrombin asshown in Example B. Gamma-thrombin, a proteolytic product ofalpha-thrombin which no longer interacts with PAR1, selectively cleavesand activates PAR4 (Soslau, G. et al., “Unique pathway ofthrombin-induced platelet aggregation mediated by glycoprotein Ib”, J.Biol. Chem., 276:21173-21183 (2001)). Platelet aggregation can bemonitored in a 96-well microplate aggregation assay format or usingstandard platelet aggregometer. The aggregation assay can also beemployed to test the selectivity of the compound for inhibiting plateletaggregation induced by PAR4 agonist peptides, PAR1 agonist peptide, ADP,or thromboxane analogue U46619.

Example C is an alpha-thrombin-induced platelet aggregation assay.Alpha-thrombin activates both PAR1 and PAR4.

Example D is a tissue factor-induced platelet aggregation assay. Theconditions in this assay mimic the physiological events during thrombusformation. In this assay, platelet aggregation in human PRP wasinitiated by the addition of tissue factor and CaCl₂. Tissue factor, theinitiator of the extrinsic coagulation cascade, is highly elevated inhuman atherosclerotic plaque. Exposure of blood to tissue factor at theatherosclerotic site triggers a robust generation of thrombin andinduces the formation of obstructive thrombi.

The efficacy of the PAR4 antagonists of the present invention inpreventing thrombosis can also be measured in a variety of in vivoassays. Exemplary mammals that can provide models of thrombosis andhemostasis to test the effectiveness of the PAR4 antagonists of thepresent invention as antithrombotic agents include, but are not limitedto, guinea pigs and primates. Relevant efficacy models include, but arenot limited to, electrolytic injury-induced carotid artery thrombosis,FeCl₃-induced carotid artery thrombosis and arteriovenous-shuntthrombosis. Models of kidney bleeding time, renal bleeding time andother bleeding time measurements can be used to assess the bleeding riskof the antithrombotic agents described in the current invention. ExampleF describes an in vivo model of arterial thrombosis in cynolmolgusmonkeys. Compounds of the present invention can be tested in this modelfor their ability to inhibit thrombus formation induced by electrolyticinjury of the carotid artery. Demonstration of efficacy in this modelsupports the utility of PAR4 antagonists of the present invention fortreatment of thromboembolic diseases.

Assays

Materials

1) PAR1 and PAR4 Agonist Peptides

SFFLRR is a known high affinity PAR1 selective agonist peptide.(Reference: Seiler, S. M., “Thrombin receptor antagonists”, Seminars inThrombosis and Hemostasis, 22(3):223-232 (1996).) The PAR4 agonistpeptides AYPGKF and H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂were synthesized. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂showed improved PAR4 agonist activity over AYPGKF in the FLIPR assay(EC₅₀ value of 8 μM forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 60 μM for AYPGKF)and in washed platelet aggregation assay (EC₅₀ value of 0.9 μM forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 12 μM forAYPGKF).

2) PAR4 Expressing Cells

HEK293 cells stably expressing PAR4 were generated by a standard methodof transfection of human PAR4 (F2R23) cDNA expression vector andselected based on PAR4 protein expression or mRNA expression. Thosecells demonstrated functional responses to PAR4 agonist peptide-inducedintracellular calcium elevation using FLIPR® (Fluorometric Imaging PlateReader; Molecular Devices Corp.). These cells also express endogenousPAR1 and can elicit calcium signal upon stimulation with PAR1 agonistpeptide. Therefore, the same cells were also used to determineselectivity against PAR1 and agonist activity for both receptors. Cellsfrom HEK293 PAR4 Clone 1.2A (BMS Arctic ID 383940) were propagated andused for calcium mobilization studies.

3) Preparation of Platelet Rich Plasma (PRP)

Human blood was collected in 3.8% sodium citrate at a ratio of 1 ml per9 ml blood and centrifuged in a Sorvall® RT6000B centrifuge at 900revolution per minute (rpm) at room temperature (RT) for 15 minutes. PRPwas collected and used for aggregation assay. Refludan (Berlex Labs,Wayne, N.J.), a recombinant hirudin, at a final concentration of 1unit/mL was added to the sample to selectively prevent PAR1 activationinduced by residual alpha-thrombin contamination. The remaining bloodsample was centrifuged at 2500 rpm at room temperature for 5 minutes tocollect platelet-poor plasma (PPP).

4) Preparation of Washed Platelets (WP)

Human blood was collected in ACD (85 mM tri-sodium citrate, 78 mM citricacid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml per 10 ml blood.PRP was isolated by centrifugation at 170 g for 14 minutes and plateletswere further pelleted by centrifugation at 1300 g for 6 minutes.Platelets were washed once with 10 ml ACD containing 1 mg/ml bovineserum albumin. Platelets were resuspended at ˜2.5×10⁸/ml in Tyrode'sBuffer (137 mM NaCl, 2 mM KCl, 1.0 mM MgCl₂, 1 mM CaCl₂, 5 mM glucose,20 mM HEPES pH 7.4).

Example A FLIPR Assay in PAR4-Expressing HEK293 Cells

FLIPR-based calcium mobilization assay in HEK293 cells was used tomeasure PAR4 antagonism, agonism, and selectivity against PAR1. Theactivity of the PAR4 antagonists of the present invention were tested inPAR4 expressing cells by monitoringH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂-induced intracellularcalcium mobilization. Counter screens for agonist activity and PAR1antagonist activity were also performed. Briefly, PAR1/PAR4-expressingHEK293 cells were grown in DMEM (Life Technology, Grand Island, N.Y.)containing 10% heat-inactivated FBS, 1% Penicillin-Streptomycin, 10μg/mL blasticidin, and 100 μg/mL Zeocin at 37° C. with 5% CO₂. Cellswere plated overnight prior to the experiment in a black 384-wellPurecoat Amine clear bottom plate (Becton Dickinson Biosciences, SanJose, Calif.) at 10,000 cells/well in 30 μL growth medium and incubatedin a humidified chamber at 37° C. with 5% CO₂ overnight. Prior tocompound addition, the cell medium was replaced with 40 L of 1× calciumand magnesium-containing Hank's Balanced Saline Solution (HBSS) (with 20mM HEPES) and 1:1000 diluted fluorescent calcium indicator (CodexBiosolutions, Gaithersburg, Md.). After a 30 minute incubation period at37° C. and a further 30 minute incubation and equilibration period atroom temperature, 20 μL test compound (diluted in 1×HBSS buffer) wasadded at various concentrations at 0.17% dimethyl sulfoxide (DMSO) finalconcentration. Changes in fluorescence intensity were measured using aFunctional Drug Screening System (FDSS, Hamamatsu, Japan) to determineagonist activities. The cells were then incubated for 30 minutes at roomtemperature followed by addition of 20 μL of agonist peptide forantagonist activity measurement. The PAR4 agonist peptide(H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂) and the PAR1agonist peptide (SFFLRR) were routinely tested to ensure a properresponse at the EC₅₀ value in the assay (˜5 μM for PAR4 agonist peptideand ˜2 μM for PAR1 agonist peptide). Compound potency was derived from11-point concentration-response curves.

Example B

Gamma Thrombin Induced Platelet Aggregation Assays

The ability of the compounds of the current invention to inhibitplatelet aggregation induced by gamma-thrombin was tested in a 96-wellmicroplate aggregation assay format. Briefly, 90 μL of PRP or washedplatelets were pre-incubated for 5 minutes at 37° C. with 3-foldserially diluted test compound, which was prepared as a 100-fold stocksolution in dimethyl sulfoxide (DMSO). Aggregation was initiated byaddition of 10 μL of gamma-thrombin (Haematologic Technologies, Inc.Essex Junction, Vt.) at 50-100 nM final concentration, which wastitrated daily to achieve 80% platelet aggregation. The plate was thenplaced into a SpectraMax® Plus Plate Reader (Molecular Devices) at 37°C. Platelet aggregation was monitored at a wavelength of 405 nm using akinetic analysis mode. Prior to the first data collection time point,the plate was shaken for 10 seconds to allow thorough mixing. Data wassubsequently collected every 10 seconds for up to 7 minutes total. Datawas collected using SoftMax® 5.4.1 software and exported to MicrosoftExcel for analysis. The optical density (OD) values at the time pointthat achieved 75% platelet activation by agonist alone were used foranalysis. The OD value from a PRP sample without any treatment served asODmaximum, and the OD value from a PPP sample containing no plateletsserved as the ODminimum. Inhibition of platelet aggregation (IPA) wascalculated based on the formula: %IPA=(100−100*[ODcompound−ODminimum]/[ODmaximum−ODminimum]). The IC₅₀value of the test compound was calculated by fitting the % IPA values tothe one-site concentration response equation: Y=A+(B−A)/{1+(C/X)̂D]},using XLfit for 32 bit Excel® Version 2 Build 30 (ID Business SolutionsLimited).

The aggregation assays were also employed to test the selectivity of thecompound against other platelet receptors by using SFFLRR for PAR1,collagen (Chrono-Log, Havertown, Pa.) for collagen receptors, ADP forP2Y1 and P2Y12 and U46619 (Cayman Chemical, Ann Arbor, Mich.) forthromboxane receptors.

Example C Alpha-Thrombin Induced Platelet Aggregation Assays

The ability of PAR4 antagonists to inhibit platelet aggregation inducedby alpha-thrombin can be tested using human washed platelets. Theantagonists are pre-incubated with washed platelets for 20 min.Aggregation is initiated by addition of 1.5 nM alpha-thrombin(Haematologic Technologies, Essex Junction, Vt.) to 300 μl of washedplatelets at stirring speed of 1000 rpm. Platelet aggregation ismonitored using an Optical Aggregometer (Chrono-Log, Havertown, Pa.) andthe area under the curve (AUC) at 6 min was measured. IC₅₀ values arecalculated using vehicle control as 0% inhibition.

Example D Tissue Factor-Induced Platelet Aggregation Assay

The ability of PAR1 or PAR4 antagonists to inhibit platelet aggregationinduced by endogenous thrombin can be tested in a tissue factor drivenaggregation assay. Aggregation is initiated by addition of CaCl₂ andrecombinant human tissue factor, which results in the generation ofthrombin through activation of the coagulation pathway in the plasma.Anticoagulant agents such as corn trypsin inhibitor (HaematologicTechnologies, Essex Junction, Vt.) at 50 μg/ml and PEFABLOC® FG(Centerchem, Norwalk, Conn.) are also added to the sample to preventfibrin clot formation during the time of the study. Platelet aggregationis monitored using standard instrumentation including opticalaggregometer or impedance aggregometer.

Example E

The following Table sets out results obtained employing variouscompounds of the invention tested in the FLIPR assay. As indicatedabove, the FLIPR assay, an in vitro assay, measures the PAR4 antagonistactivity of compounds tested as described in Example A.

TABLE 2 PAR4 FLIPR assay Example (EC₅₀, nM) 1 1.1 2 1.0 3 2.6 4 17 5 1.36 1.4 7 10 8 1.6 9 2.0 10 1.9 11 1.7 12 1.5 13 1.9 14 1.4 15 1.7 16 1.417 0.55 18 0.91 19 3.3 20 1.4 21 1.5 22 1.1 23 1.8 24 1.4 25 1.7 26 0.7527 0.87 28 2.0 29 1.1 30 1.8 31 1.3 32 1.6 33 1.8 34 1.2 35 1.0 36 2.537 2.5 38 4.8 39 2.4 40 1.4 41 1.4 42 2.3 43 1.6 44 2.3 45 2.8 46 1.1 476.9 48 2.7 49 0.85 50 7.4 51 2.3 52 0.41 53 3.5 54 NT 55 1.1 56 5.5 571.8 58 0.74 59 3.5 60 2.9 61 1.5 62 57 63 1.4 64 1.4 65 1.1 66 5.7 67680 68 8.9 69 12 70 1.0 71 1.9 72 2.2 73 3.6 74 0.95 75 1.7 76 2.5 77120 78 2.3 79 NT 80 94 81 4.8 82 5.2 83 4.1 84 2.5 85 6.1 86 1.8 87 5.788 3.3 89 3.5 90 1.1 91 2.0 92 3.5 93 4.8 94 3.8 95 NT 96 NT 97 2.5 98NT 99 NT 100 NT 101 3.1 102 4.1 103 4.5 104 2.2 105 3.4 106 1.5 107 26108 NT 109 NT 110 0.52 111 6.0 112 0.55 113 NT 114 37 115 96 116 140117 >3300 118 16 119 1700 120 4.2 121 140 122 5.0 123 5.0 124 190 1253.9 126 260 127 2.9 128 >3300 129 4.2 130 5.2 131 NT 132 3.8 133 2.7 1345.0 135 5.0 136 3.9 137 3.4 138 2.5 139 2.7 140 1.5 141 1.9 142 1.3 1435.9 144 3.8 145 6.8 146 7.5 147 1.6 148 6.8 149 2.0 150 2.3 151 3.4 1521.3 153 0.99 154 2.2 155 2.3 156 1.7 157 2.8 158 12 159 1.6 160 36 1611.5 162 11 163 2.1 164 2.0 165 4.6 166 2.3Data in Table 2 are reported with two significant figures. NT indicatesthe compound was not tested in the FLIPR assay.

Example F Cynomolgus Monkey Electrolytic Injury-Induced Carotid ArteryThrombosis Model

Healthy cynomolgus monkeys can be used in the study. These monkeys areretired from other pharmacokinetic and pharmacodynamic studies and hadat least a 4-week washout period.

On the day of the study, compounds or vehicles are administered orallyat 1 to 2 hours before the experiment. Monkeys are then sedated byintramuscular administration of 0.2 mg/kg atropine, 5 mg/kg TELAZOL®(tiletamine/zolazepam) and 0.1 mg/kg hydromorphone to facilitateplacement of an endotracheal tube. An intravenous catheter is placed inthe left cephalic vein for fluid administration to prevent dehydration.Animals are then administered with an inhalant anesthetic, isoflurane(1-5% to effect) and oxygen, ventilated, and placed on athermostatically controlled heating pad to maintain the body temperatureat 37° C. General anesthesia is maintained at a surgical plane usinginhaled isoflurane and oxygen. The left brachial artery is cannulated torecord blood pressure and heart rate. Blood pressure and heart rate aremonitored to maintain normal vital signs.

The carotid arterial thrombosis model in monkeys is based on a rabbitarterial thrombosis model, as described by Wong et al. (Wong, P. C. etal., “Nonpeptide factor Xa inhibitors: II. Antithrombotic evaluation ina rabbit model of electrically induced carotid artery thrombosis”, J.Pharmacol. Exp. Ther., 295:212-218 (2002).) Thrombosis is induced byelectrical stimulation of the carotid artery for 5 min at 10 mA using anexternal stainless-steel bipolar electrode. Carotid blood flow ismeasured with an appropriately sized TRANSONIC® flow probe and aTRANSONIC® perivascular flowmeter (TS420 Model, Transonic Systems Inc.,Ithaca, N.Y.). It is continuously recorded over a 90-min period tomonitor thrombosis-induced occlusion. Integrated carotid blood flow ismeasured by the area under the flow-time curve. It is expressed aspercent of total control carotid blood flow, which would result ifcontrol blood flow had been maintained continuously for 90 min. Inaddition, thrombus from the injured artery is removed, blotted twice ona weighing paper to remove residual fluid, and weighed.

While it is apparent that the embodiments of the application hereindisclosed are well suited to fulfill the objectives stated above, itwill be appreciated that numerous modifications and other embodimentsmay be implemented by those skilled in the art, and it is intended thatthe appended claims cover all such modifications and embodiments thatfall within the true spirit and scope of the present application.

1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein: the dashed line represents an optionaldouble-bond with the proviso that only one of the two dashed line doublebonds exists at the same time; X¹ is O and X² is CR^(1a) or N; or X¹ isN and X² is O; or X¹ is N or CR^(1a), and X² is S; or X¹ is N and X² isNR⁸; or X¹ is NR⁸ and X² is N; or X¹ is NR⁸ and X² is CR^(1a); or X¹ isCR^(1a) and X² is NR⁸; Y is S or —CR^(2a)═CR^(2a)—; X³, X⁴ and X⁵ areindependently selected from C(R⁹) or N; W is O or S; R¹ is—N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom, or alternatelythe moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy; R² is H, halo, C₁-C₆ alkyl,C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl; R^(2a) is independently at eachoccurrence selected from the group consisting of H, halo, CN, C₁-C₃alkyl, C₁₋₃ haloalkyl, C₁-C₃ alkoxy, and C₁-C₃ haloalkoxy; R³ isselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₃-C₆ cycloalkyl, C₂-C₃alkenyl, C₂-C₃ alkynyl and halo; R⁴ and R⁵ are independently selectedfrom H, C₁-C₆ alkyl, C₁-C₄ fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴and R⁵ can be taken together with the carbon to which they are attachedto form a C₃-C₇ cycloalkyl ring; R⁶ is selected from H, C₁-C₆ alkyl,C₁-C₃ haloalkyl, or C₁-C₃hydroxyalkyl; and R⁷ is selected from the groupconsisting of hydrogen, C₂-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7membered heterocyclic ring containing 1-3 hetero atoms independentlyselected from N, O or S, C₃₋₇ cycloalkyl, and 6-10 membered heteroaryl,wherein each of said alkyl, cycloalkyl, aryl, heterocylic and heteroarylgroup is independently unsubstituted or substituted with 1-3 moietieswhich can be the same or different and being independently selected fromthe group consisting of halo, alkyl, haloalkyl, aryl, heteroaryl,alkoxy, haloalkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹, NR¹⁰COR¹¹,NR¹⁰CONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy, wherein R¹⁰ and R¹¹are the same or different and are H or C₁₋₄ alkyl or R¹⁰ and R¹¹ can betaken together with the N to which they are attached to form a 4-7membered heterocycle ring; or R⁶ and R⁷ may be taken together to form amonocyclic or bicyclic heterocyclic ring with 0-2 additional heteroatomsselected independently from N, O, or S, wherein each of said monocyclicor bicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹²SO₂R¹³, NR¹²COR¹³,NR¹²CONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³are the same or different and are H or C₁₋₄ alkyl, or R¹² and R¹³ can betaken together with the N to which they are attached to form a 4-7membered heterocycle ring, R⁸ is H or C₁-C₄ alkyl; and R⁹ is selectedfrom the group consisting of H, halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl,—C₁-C₆ alkoxy and C₁-C₃ haloalkoxy; with the proviso that when Y is Sand A is

then R⁷ is not pyridizin-4-yl.
 2. The compound of claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof, wherein: X¹ is O and X² is CR^(1a) or N; or X¹ is N andX² is O; or X¹ is N or CR^(1a), and X² is S.
 3. The compound of claim 1,or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein the compound has Formula IA:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein: the dashed line represents an optionaldouble-bond with the proviso that only one of the two dashed line doublebonds exists at the same time; X¹ is O and X² is CR^(1a) or N; or X¹ isN and X² is O; or X¹ is N or CR^(1a), and X² is S; X³, X⁴ and X⁵ areindependently selected from C(R⁹) or N; W is O or S; R¹ is—N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom, or alternatelythe moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy; R² is H, halo, C₁-C₆ alkyl,C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl; R³ is selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₂ haloalkyl,C₁₋₂ haloalkoxy, C₃₋₆ cycloalkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl and halo;R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring; R⁸ is H or C₁-C₄ alkyl; R⁹ is selected from the group consistingof H, halo, C₁-C₆ alkyl, haloC₁₋₆ alkyl, —O—(C₁-C₆ alkyl) and haloC₁₋₃alkoxy; R⁶ is selected from H, C₁-C₆ alkyl, haloC₁₋₃alkyl, orhydroxyC₁₋₃alkyl; and R⁷ is selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 memberedheterocyclic ring containing 1-3 moieties independently selected from N,O or S, C₃₋₇ cycloalkyl, and 6-10 membered heteroaryl, wherein each ofsaid alkyl, aryl, heterocylic and heteroaryl is independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyloxy,alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro,cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH,COOR¹⁰, oxo and methylenedioxy, wherein R¹⁰ and R¹¹ are the same ordifferent and are H or C₁₋₄ alkyl or R¹⁰ and R¹¹ can be taken togetherwith the N they are attached to to form a 4-7 membered heterocycle ring;or R⁶ and R⁷ may be taken together to form a monocyclic or bicyclicheterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, COOH, COOR¹², oxo andmethylenedioxy, wherein R¹² and R¹³ are the same or different and are Hor C₁₋₄ alkyl, or R¹² and R¹³ can be taken together with the N to whichthey are attached to form a 4-7 membered heterocycle ring, with theproviso that when A is

then R⁷ is not pyridizin-4-yl.
 4. The compound of claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof, wherein the compound has Formula IB:

wherein: the dashed line represents an optional double-bond with theproviso that only one of the two dashed line double bonds exists at thesame time; X¹ is O and X² is CR^(1a) or N; or X¹ is N and X² is O; or X¹is N or CR^(1a), and X² is S; X³, X⁴ and X⁵ are independently selectedfrom C(R⁹) or N; W is O or S; R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom, or alternatelythe moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy; R² is H, halo, C₁-C₆ alkyl,C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl; R³ is selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₂ haloalkyl,C₁₋₂ haloalkoxy, C₃₋₆ cycloalkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl and halo;R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring; R⁸ is H or C₁-C₄ alkyl; R⁹ is selected from the group consistingof H, halo, C₁-C₆ alkyl, haloC₁₋₆ alkyl, —O—(C₁-C₆ alkyl) and haloC₁₋₃alkoxy; R⁶ is selected from H, C₁-C₆ alkyl, haloC₁₋₃alkyl, orhydroxyC₁₋₃alkyl; and R⁷ is selected from the group consisting ofhydrogen, C₂-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 memberedheterocyclic ring containing 1-3 moieties independently selected from N,O or S, C₃₋₇ cycloalkyl, and 6-10 membered heteroaryl, wherein each ofsaid alkyl, aryl, heterocylic and heteroaryl is independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyloxy,alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro,cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH,COOR¹⁰, oxo and methylenedioxy, wherein R¹⁰ and R¹¹ are the same ordifferent and are H or C₁₋₄ alkyl, or R¹⁰ and R¹¹ can be taken togetherwith the N to which they are attached to form a 4-7 membered heterocyclering; or R⁶ and R⁷ may be taken together to form a monocyclic orbicyclic heterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, COOH, COOR¹², oxo andmethylenedioxy, wherein R¹² and R¹³ are the same or different and are Hor C₁₋₄ alkyl or R¹² and R¹³ can be taken together with the N to whichthey are attached to form a 4-7 membered heterocycle ring.
 5. Thecompound of claim 1, or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate or prodrug thereof, wherein: the compound hasFormula IC:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein: the dashed line represents an optionaldouble-bond with the proviso that only one of the two dashed line doublebonds exists at the same time; X¹ is O and X² is CR^(1a) or N; or X¹ isN and X² is O; or X¹ is N or CR^(1a), and X² is S; W is O; R¹ is—N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom, or alternatelythe moiety

is selected from

R^(1a) is selected from the group consisting of H, halo, cyano, C₁-C₄alkyl, C₃-C₅ cycloalkyl and C₁-C₄ alkoxy; R² is H, halo, C₁-C₆ alkyl,C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl; R³ is selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₂ haloalkyl,C₁₋₂ haloalkoxy, C₃₋₆ cycloalkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl and halo;R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴ and R⁵ can be taken togetherwith the carbon to which they are attached to form a C₃-C₇ cycloalkylring; R⁸ is H or C₁-C₄ alkyl; R⁹ is selected from the group consistingof H, halo, C₁-C₆ alkyl, haloC₁₋₆ alkyl, —O—(C₁-C₆ alkyl) and haloC₁₋₃alkoxy; R⁶ is selected from H, C₁-C₆ alkyl, haloC₁₋₃alkyl, orhydroxyC₁₋₃alkyl; and R⁷ is selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 memberedheterocyclic ring containing 1-3 moieties independently selected from N,O or S, C₃₋₇ cycloalkyl, and 6-10 membered heteroaryl, wherein each ofsaid alkyl, aryl, heterocylic and heteroaryl is independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyloxy,alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro,cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH,COOR¹⁰, oxo and methylenedioxy, wherein R¹⁰ and R¹¹ are the same ordifferent and are H or C₁₋₄ alkyl, or R¹⁰ and R¹¹ can be taken togetherwith the N to which they are attached to form a 4-7 membered heterocyclering; or R⁶ and R⁷ may be taken together to form a monocyclic orbicyclic heterocyclic ring with 0-2 additional hetero atoms selectedindependently from N, O, or S, wherein each of said monocyclic orbicyclic heterocylic ring can be independently unsubstituted orsubstituted with 1-3 moieties which can be the same or different andbeing independently selected from the group consisting of halo, alkyl,aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy, alkyloxycarbonyl,alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂,NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, COOH, COOR¹², oxo andmethylenedioxy, wherein R¹² and R¹³ are the same or different and are Hor C₁₋₄ alkyl, or R¹² and R¹³ can be taken together with the N to whichthey are attached to form a 4-7 membered heterocycle ring.
 6. Thecompound of claim 1, or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate or prodrug thereof, wherein the compound hasFormula ID:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein: the dashed line represents an optionaldouble-bond with the proviso that only one of the two dashed line doublebonds exists at the same time; X¹ is O and X² is CR^(1a) or N; or X¹ isN and X² is O; or X¹ is N or CR^(1a), and X² is S; W is O; R¹ is—N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom, or alternatelythe moiety

is selected from

R^(1a) is selected from the group consisting of H, or methyl; R² is H,or methyl; R³ is selected from the group consisting of methyl, ethyl,methoxy, 1,1-difluoroethyl, or 1-fluoroethyl; R⁴ and R⁵ areindependently selected from H or methyl; R⁸ is H or methyl; R⁹ ismethoxy; R⁶ is selected from H or methyl; R⁷ is selected from the groupconsisting of hydrogen, C₂-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7membered heterocyclic ring containing 1-3 moieties independentlyselected from N, O or S, C₃₋₇ cycloalkyl, and 6-10 membered heteroaryl,wherein each of said alkyl, aryl, heterocylic and heteroaryl isindependently unsubstituted or substituted with 1-3 moieties which canbe the same or different and being independently selected from the groupconsisting of halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy,arylalkyloxy, alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl,arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹⁰R¹¹,SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy, wherein R¹⁰ and R¹¹ arethe same or different and are H or C₁₋₄ alkyl, or R¹⁰ and R¹¹ can betaken together with the N to which they are attached to form a 4-7membered heterocycle ring; or R⁶ and R⁷ may be taken together to form amonocyclic or bicyclic heterocyclic ring with 0-2 additional heteroatoms selected independently from N, O, or S, wherein each of saidmonocyclic or bicyclic heterocylic ring can be independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy,alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro,cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, COOH,COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³ are the same ordifferent and are H or C₁₋₄ alkyl, or R¹² and R¹³ can be taken togetherwith the N to which they are attached to form a 4-7 membered heterocyclering, with the proviso that when A is

then R⁷ is not pyridizin-4-yl.
 7. The compound of claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof, wherein the compound of Formula I is selected from thecompounds of formulas IE, IF, IG, IH and IJ:

wherein the various moieties are independently selected and are asdefined earlier in claim 1, with the proviso that when A

then R⁷ is not pyridizin-4-yl.
 8. The compound of claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof, wherein the compound of Formula I is selected from thecompounds of formulas IN, IO, IP, IQ and IR:

wherein the various moieties are independently selected and are asdefined earlier in claim
 1. 9. The compound of claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof, wherein the various moieties are independentlyselected, and X³, and X⁵ are CH; X⁴ is CR⁹; W is O; Y is S or —CH═CH—;R^(1a) is H; R² is H; R³ is —OCH₃ or CH₃; R⁴ and R⁵ are H; R⁶ is H ormethyl; R⁹ is —OCH₃; R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom; or alternatelythe moiety

is selected from

and R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl,or R¹⁰ and R¹¹ can be taken together with the N to which they areattached to form a 4-7 membered heterocycle ring; or R⁶ and R⁷ may betaken together to form a monocyclic or bicyclic heterocyclic ring with0-2 additional hetero atoms selected independently from N, O, or S,wherein each of said monocyclic or bicyclic heterocylic ring can beindependently unsubstituted or substituted with 1-3 moieties which canbe the same or different and being independently selected from the groupconsisting of halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy,arylalkyoxy, alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl,arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³,SONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³ arethe same or different and are H or C₁₋₄ alkyl, or R¹² and R¹³ can betaken together with the N to which they are attached to form a 4-7membered heterocycle ring.
 10. The compound of claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof, wherein the various moieties are independentlyselected, and X³═X⁵═CH; X⁴ is CR⁹; W is O; Y is S; R^(1a) is H; R² is H;R³ is CH₃ or methoxy; R⁴ and R⁵ are H; R⁶ is H; R⁹ is methoxy; R¹ is—N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom; or alternatelythe moiety

is selected from

and R⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl,or R¹⁰ and R¹¹ can be taken together with the N to which they areattached to form a 4-7 membered heterocycle ring; or R⁶ and R⁷ may betaken together to form a monocyclic or bicyclic heterocyclic ring with0-2 additional hetero atoms selected independently from N, O, or S,wherein each of said monocyclic or bicyclic heterocylic ring can beindependently unsubstituted or substituted with 1-3 moieties which canbe the same or different and being independently selected from the groupconsisting of halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy,arylalkyoxy, alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl,arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³,SONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³ arethe same or different and are H or C₁₋₄ alkyl, or R¹² and R¹³ can betaken together with the N to which they are attached to form a 4-7membered heterocycle ring.
 11. The compound of claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof, wherein the various moieties are independentlyselected, and X³═X⁵═CH; X⁴ is CR⁹; W is O; Y is S; R^(1a) is H; R² is H;R³ is CH₃ or methoxy; R⁴ and R⁵ are H; R⁶ is H; R⁹ is methoxy; R¹ is—N(R⁶)—C(O)—R⁷;

is selected from the group consisting of a phenyl or pyridyl ring; andR⁷ is selected from the group consisting of hydrogen, C₂-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7 membered heterocyclic ring containing 1-3moieties independently selected from N, O or S, C₃₋₇ cycloalkyl, and6-10 membered heteroaryl, wherein each of said alkyl, aryl, heterocylicand heteroaryl is independently unsubstituted or substituted with 1-3moieties which can be the same or different and being independentlyselected from the group consisting of halo, alkyl, aryl, heteroaryl,alkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, COOH, COOR¹⁰, oxo and methylenedioxy,wherein R¹⁰ and R¹¹ are the same or different and are H or C₁₋₄ alkyl,or R¹⁰ and R¹¹ can be taken together with the N to which they areattached to form a 4-7 membered heterocycle ring; or R⁶ and R⁷ may betaken together to form a monocyclic or bicyclic heterocyclic ring with0-2 additional hetero atoms selected independently from N, O, or S,wherein each of said monocyclic or bicyclic heterocylic ring can beindependently unsubstituted or substituted with 1-3 moieties which canbe the same or different and being independently selected from the groupconsisting of halo, alkyl, aryl, heteroaryl, alkoxy, aryloxy,arylalkyoxy, alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl,arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³,SONR¹²R¹³, COOH, COOR¹², oxo and methylenedioxy, wherein R¹² and R¹³ arethe same or different and are H or C₁₋₄ alkyl, or R¹² and R¹³ can betaken together with the N to which they are attached to form a 4-7membered heterocycle ring.
 12. A compound, or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug thereof, whereinthe compound has the formula:

wherein: X³, X⁴ and X⁵ are independently selected from C(R⁹) or N; W isO or S; R¹ is —N(R⁶)—C(O)—R⁷ or —N(R⁶)—S(O)₂—R⁷;

is selected from the group consisting of a phenyl ring, or a 6-memberedheteroaryl ring containing at least one nitrogen atom, or alternatelythe moiety

is selected from

R² is H, halo, C₁-C₆ alkyl, C₁-C₃ alkoxy, CN or C₃-C₇ cycloalkyl; R³ isselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₃-C₆ cycloalkyl, C₂-C₃alkenyl, C₂-C₃ alkynyl and halo; R⁴ and R⁵ are independently selectedfrom H, C₁-C₆ alkyl, C₁-C₄ fluoroalkyl, and C₁-C₄ hydroxyalkyl, or R⁴and R⁵ can be taken together with the carbon to which they are attachedto form a C₃-C₇ cycloalkyl ring; R⁶ is selected from H, C₁-C₆ alkyl,C₁-C₃ haloalkyl, or C₁-C₃hydroxyalkyl; and R⁷ is selected from the groupconsisting of hydrogen, C₂-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₇ alkoxy, 5-7membered heterocyclic ring containing 1-3 atoms independently selectedfrom N, O or S, C₃₋₇ cycloalkyl, and 6-10 membered heteroaryl, whereineach of said alkyl, cycloalkyl, aryl, heterocylic and heteroaryl groupis independently unsubstituted or substituted with 1-3 moieties whichcan be the same or different and being independently selected from thegroup consisting of halo, alkyl, haloalkyl, aryl, heteroaryl, alkoxy,haloalkoxy, aryloxy, arylalkyloxy, alkyloxycarbonyl, alkylcarboxy,aryloxycarbonyl, arylcarboxy, nitro, cyano, OH, NH₂, NH(alkyl),N(alkyl)₂, CONR¹⁰R¹¹, SONR¹⁰R¹¹, NR¹⁰SO₂R¹¹, NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹,COOH, COOR¹⁰, oxo and methylenedioxy, wherein R¹⁰ and R¹¹ are the sameor different and are H or C₁₋₄ alkyl, or R¹⁰ and R¹¹ can be takentogether with the N to which they are attached to form a 4-7 memberedheterocycle ring; or R⁶ and R⁷ may be taken together to form amonocyclic or bicyclic heterocyclic ring with 0-2 additional heteroatoms selected independently from N, O, or S, wherein each of saidmonocyclic or bicyclic heterocylic ring can be independentlyunsubstituted or substituted with 1-3 moieties which can be the same ordifferent and being independently selected from the group consisting ofhalo, alkyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyoxy,alkyloxycarbonyl, alkylcarboxy, aryloxycarbonyl, arylcarboxy, nitro,cyano, OH, NH₂, NH(alkyl), N(alkyl)₂, CONR¹²R¹³, SONR¹²R¹³, NR¹⁰SO₂R¹¹,NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, COOH, COOR¹², oxo and methylenedioxy, whereinR¹² and R¹³ are the same or different and are H or C₁₋₄ alkyl, or R¹²and R¹³ can be taken together with the N to which they are attached toform a 4-7 membered heterocycle ring; R⁸ is H or C₁-C₄ alkyl; and R⁹ isselected from the group consisting of H, halo, C₁-C₆ alkyl, C₁₋₆haloalkyl, —C₁-C₆ alkoxy and C₁-C₃ haloalkoxy, with the proviso thatwhen the compound is:

and A is

then R⁷ is not pyridizin-4-yl.
 13. The compound as defined in claim 1,wherein the compound is selected from Examples 1-166.
 14. Apharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a compound as defined in claim 1, or astereoisomer, tautomer, pharmaceutically acceptable salt, or solvatethereof, alone or in combination with another therapeutic agent.
 15. Amethod of treating a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder comprising administering atherapeutically effective amount of a compound as defined in claim 1, ora stereoisomer, tautomer, pharmaceutically acceptable salt, or solvatethereof, to a subject in need thereof, wherein the thromboembolicdisorder is selected from the group consisting of arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, cerebrovascular thromboembolic disorders, andthromboembolic disorders in the chambers of the heart or in theperipheral circulation.
 16. A method of inhibiting or preventingplatelet aggregation comprising administering a therapeuticallyeffective amount of a compound as defined in claim 1, or a stereoisomer,tautomer, pharmaceutically acceptable salt, or solvate thereof, to asubject in need thereof.
 17. A method of treating a thromboembolicdisorder or the primary or secondary prophylaxis of a thromboembolicdisorder comprising administering the pharmaceutical composition asdefined in claim 14, wherein the thromboembolic disorder is selectedfrom the group consisting of arterial cardiovascular thromboembolicdisorders, venous cardiovascular thromboembolic disorders,cerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation.
 18. Amethod of inhibiting or preventing platelet aggregation comprisingadministering the pharmaceutical composition as defined in claim 14.